Once the episcopal seat of the influential Prince-Electors, the "civilized" origins of Mainz date back to around 38 BC, when the Romans built a citadel here. The city's location at the confluence of the Rhine and the Main is ideal for trade, something reflected by the artifacts kept in the Landesmuseum, that show there have been settlements here since 300,000 BC.
The most logical starting point is the Dom, the Cathedral of St Martin and St Stephan, especially on Tuesdays, Fridays, and Saturdays, when the farmers' market is open. Although the cathedral was actually started in 975, most of what is seen today was built from the 11th to the 13th centuries. At the Dom und Diözesanmuseum in the cathedral cloisters, you can truly witness the opulence and wealth controlled by the Church in Mainz.
Mainz is also the home of the man identified by Time Magazine as the most important individual in the last millennium, Johannes Gutenberg, the inventor of the moveable type printing press.
Mainz is also the home of the music publisher Schott Music.
From Frankfurt International Airport, the local train S8 towards Wiesbaden stops at Mainz Hauptbahnhof (or optionally Mainz Römisches Theater). The train runs at least every 30 minutes daily, and takes around 30 minutes to get the Mainz. Also regional trains towards Koblenz and Saarbrücken stop in Mainz. Both options share the same local tariff, regional trains are faster and somewhat more convenient. Cologne/Bonn Airport is served by a direct ICE connection and from low cost hub Frankfurt-Hahn Airport there is a direct shuttle bus connection.
Mainz has several railway stations. The biggest and the only one in which InterCity and InterCityExpress trains do stop is Mainz Hauptbahnhof (main station), it is on the western edge of the city centre and works as a general hub for local traffic. Another noteworthy station is Mainz Römisches Theater (Roman theatre), south of the centre, but it is only served by regional and commuter trains. Both are served from Frankfurt, about 45 minutes away, by S-Bahn line S8.
A number of long range buses (including Eurolines) serve Mainz, usually stopping at Hauptbahnhof. The station is also a hub for local bus traffic, serving the surrounding countryside and Wiesbaden.
From Frankfurt Hahn Airport for those arriving with Ryanair, there is a direct bus service to Mainz roughly every 90 minutes. The ORN bus stop which services this route is just outside the main railway station's police office. The service takes aprox. 60-70 mins .
There is a number of companies offering river cruises, typically leaving from Cologne or Koblenz and terminating in Mainz (and vice versa). The KD Rhine River Cruise Pass offers a cruise of the Rhine river around all the way to Cologne with the possibility of stops along the way.
The centre of town is accessible on foot from Mainz Haufbahnhof. There are signposts and maps throughout the city centre, or you can pick up a map from the DB information desk in the station.
Some good offers to explore the surroundings include the Rheinland-Pfalz-Ticket, offering unlimited travel in local trains for up to 5 persons inside the states of Rhineland-Palatinate, Saarland and Wiesbaden. The ticket costs 21 - 37 € per day (as of Jan. 2012) if bought via automat or internet, or 23 - 39 € if bought at a ticket stand and is available at all railway stations. For Hessen (including Mainz, but not the rest of Rhineland-Palatinate) exists the otherwise similar Hessenticket, costing 31 € per day.
Dom St. Martin (Romanesque cathedral) – one of Germany's oldest and is currently covered with unsightly scaffolding [Sept 2012] along with the others in: Worms, Speyer
"Stephanskirche", world-famous Chagall windows (blue).
Christuskirche (Christ Church) - Italian renaissance on the Rhine
Mainz Synagogue, one of the most interesting new synagogues recently constructed in Germany, and maybe even worldwide. By the architect Manuel Herz. 
River Banks with lots of restaurants and (night) clubs.
The 'Theodor-Heuss-Bridge' in the centre of Mainz.
The Theodor Heuss Rhine Bridge between Mainz and Mainz-Kastel is one of three Rhine bridges that connect Mainz with Wiesbaden and the state of Hesse. Like almost all other German Rhine bridges, the former bridge had been destroyed in World War II. The bridge was rebuilt in the early 1950s and named after the first president of the Federal Republic of Germany, Theodor Heuss. Kastel, a former Mainz suburb and several other villages on the right side of the Rhine, has been separated from the city after the war, as the Rhine was the border between the French and American occupation sectors. Even today, Kastel, Kostheim, Amoeneburg, Ginsheim, Gustavsburg and the other former suburbs consider themselves part of Mainz, although they are administered by Wiesbaden and Hesse.
Mainz City Hall.
The City Hall was built in the early 1970s by Danish architects, who used many tons Swedish marble for the facade. Considered modern at the time it was built, the city hall is not very popular today, many consider it too monumental, some even ugly. From the extensive city hall platform there is a beautiful view on the Rhine promenade and the river.
Schillerplatz. Beautiful, leafy square in central Mainz with the fountain said to represent the jesters and fun of Mainz's fastnacht celebration.
Gutenberg Museum (Liebfrauenplatz 5, Ph: +49 6131 1266-4044,), there are reconstructions of print shops and Gutenberg's hand press, an exhibition of incunabula, and the first two Gutenberg bibles are on display in a strong room. They also have a section devoted to the far East with colored woodcarvings and prints from Japan, China and Korea. There is even an exhibition on the electronic future of books. Most displays have an English translation. You can purchase a guide in several different languages with your admission.
Römisch-Germanisches Zentralmuseum (Roman-Germanic Museum) - Tu-Su 10AM to 6PM  - Kurfürstliches Schloss
Unique to Mainz is the Museum für Antike Schifffahrt – The Museum of Ancient Sea Travel contains the remains of five 5th century 6 Roman warship wrecks salvaged from the Rhine in the 1980’s. True-to-life replicas were re-constructed based on these originals. Visitors also have the opportunity to glimpse behind the scenes in the research laboratory and in the museum’s workshops. These ships were found when the local Hilton was expanding its property. - Tuesday to Sunday 10AM to 6PM - Neutorstr. 2b 
The Sacred Site of Isis- Mater Magna - Monday to Saturday, 10AM to 6PM - Free of charge - Römerpassage 1
Dommuseum (Church art)
Naturhistorisches Museum (Museum of Natural History)
Walk around the town. All the major attractions are easily reached on foot, on nice days walking & sitting along the Rhine river is a great way to pass an afternoon.
Go and explore the outdoor town market on Tuesdays, Fridays, and Saturdays at the cathedral.
Visit the small but very nice Altstadt(old-town) of Mainz. Located just behind the cathedral with a beautiful baroque church and a number of well preserved Fachwerkhäuser (Medieval style houses) to be seen.
Go to see a football match of the Bundesliga-club 1. FSV Mainz 05 in its new stadium.
Mainz has two culinary specialities, both types of cheese. Spundekäse is local cream cheese whipped with cream into a soft paste, served with chopped raw onion and pretzels — the taste is mild and it goes great with beer.
Handkäse is a sour milk cheese with a pungent aroma, most often served mit Musik, or marinated in vinegar and oil, then sprinkled with caraway seeds, resulting in a bizarre, firm, gelatinous mass that most people find to be a bit of an acquired taste — and the "music" refers to the flatulence it tends to cause!
Best Worscht In Town (Curry Wurst Place), Augustinerstraße 9, Mainz Old Town (5 minutes from Römisches Theater), . Best place in Mainz for a curry wurst. Although a Frankfurt specialty, the location is ideal and a popular hang out for locals. Best Worscht is known for its "hotness" scale ranging from A to F, with F being unbearably hot! Closed on Sundays.6€ for snackers combo. edit
Burgerladen, Quintinsstraße 7, . New burger establishment, run be young Mainzers with a focus on organic produce. Best bet is the "Burger der Woche" (Burger of the week) in a menu with drink and chips 8.50€. Open late, popular with students, limited seating. edit
Haus des Weines, Gutenbergplatz 3. Phone: +49 6131 221300. Open late, they offer a great selection of wines to go with their delicious food that ranges from snacks to full meals and tends to focus on regional cuisine.
Geberts Weinstuben, Frauenlobstraße 94. Phone: +49 6131 611619, fax: +49 6131 611662, firstname.lastname@example.org. With an excellent wine list (heavy on German wines), Geberts offers excellent versions of traditional regional favorites, including handkäs-Suppe (cheese soup) and wildschwein (wild boar). They are closed for three weeks during the summer, on Saturdays, and at lunchtime on Sundays.
Heiliggeist, Mailandsgasse 11. Phone: +49 6131 225757. Recently renovated into an upscale bistro, they offer an abbreviated, but very creative menu that goes with an extensive wine list, including wines by the glass, that enable you to experiment wines from around Germany.
Fisch Jackob, Fischtorstraße 7. Phone: +49 6131 229299 . A very nice fish restaurant which offers nice shell filett, mussels in white whine and zander. The wines are mostly from the region and it is possible to sit outside. Closed on Sundays
Brauhaus zur Sonne, Sonnengäßchen 2, 55116 Mainz (Between Kaufhof and C&A), ☎ +49 6131 231610, . Mon-Sat 11-11. Friendly place serving local specialties.edit
Fiszbah, Raimundistr. 13, ☎ +49 6131 670330, . Weekdays 7PM-late, weekends from 9AM. Legendary little dive bar with hot waitresses, cold beer, interesting people and wildly diverse music (e.g. "Discopogo for Punks in Pumps" on Tuesdays). Limited food menu and breakfast/brunch on weekends as well. edit
Hafeneck, Frauenlobstr. 93, ☎ +49 6131 4801977, . Neighborhood bar that manages to simultaneously cater to football fans, local hipsters and an endless streams of niche musicians ranging from the "Whiskey Rabbi" to Vicky Vomit. The kitchen (open 5-11PM daily) also serves up huge salads, a few German classics like schnitzel, plus giant savoury pancakes (Eierpfannkuchen) with unusual fillings, many of them vegetarian — try the "Hades" to add some spice to your life.edit
Pourist, Heugasse 6, ☎ +49 171 4577339, . A really nice spot in Mainz where it is allowed to smoke. Probably the best cocktails in town. Friendly barkeepers and guests. edit
Eisgrub-Bräu, Mainz Weissliliengasse 1a, . This cavernous "ice cellar" has brewed its own beer since 1872 and is still packed most nights. In addition to their own beers, pale and dark, they also serve up hearty portions of honest German grub.
Good Time and Alexander the Great, Hintere Bleiche 18a and 8. Popular Hard Rock pubs quite close to the main railway station. They serve mead in horns and play anything from Death Metal to classical music (depending on the day of the week)!
Mainz Kastel Brauhaus, located on the Otto Suhr Ring Road (Wiesbaden Mainz-Kastel), 2 blocks(right) off the main Hwy B455 going to Wiesbaden, from Mainz across the Theodore Heuss Brucke-1K. You can see the Biergarten's Umbrellas using Google Earth. It is the German equivalent of an American Microbrew Pub/Restaurant. Their light (hell) beer with Mainz's famous Spundekase and pretzels is great. Well worth the visit.
Restaurant "19" Mainzer Golfclub, 55257 Budenheim Oberer Mombacher Weg 4, . Homebrew "Club-Bier" - naturtrübes Pils. More than 60 Craft-Beer's - Unique in Germany. Great Beergarden. Fresh & Local Cuisine.
Jugendherberge Mainz (Youth Hostel), Otto-Brunfels-Schneise 4, ☎ +49 6131 85332 (email@example.com), . Beautifully located between the river Rhine and the People's Park with two bus stops nearby.edit
Hotel Ibis Holzhofstraße 2
Located just a few blocks outside of the Altstadt and a block from the Rhein, Hotel Ibis is always a pleasant experience. Very friendly, multilingual staff. Free wifi in the lobby.
Hyatt Regency Mainz, Malakoff-Terrasse 1, ☎ +49 6131 731234 (firstname.lastname@example.org), . Incorporates Fort Malakoff, Mainz's 19th-century castle, into its 21st-century architecture. It's the only 5 star hotel in Mainz on the river Rhine.edit