From Istanbul to Cairo
Istanbul - Cairo is a classic overland route. It is a route that has been traveled for centuries, particularly during the Ottoman empire. Historically it overlapped with the Hajj, with many people covering all or part of the route as part of their pilgrimage to Mecca.
Backpackers discovered it in the '70s and '80s, with hippies searching for spiritual peace who departed to Jerusalem from Istanbul instead of going to India via Iran, Afghanistan and Pakistan. After the peace treaty between Egypt and Israel, onward travel from Jerusalem to Cairo became a possibility. For visa reasons (see below) the route is almost always traveled Istanbul-Cairo, few choose to go the opposite direction. The guide book series Lonely Planet made the route even more popular by publishing their "Istanbul to Cairo on a shoestring".
See also Tips for travel in developing countries; advice there applies to most of this route.
It is essential to have a good guidebook and learn some basic rules of Middle Eastern etiquette. Like don't use your left hand, because it is considered dirty and do not put your feet up on furniture used as a foot stool. (Traditionally the left hand is used to clean yourself with water after using the toilet.) Always wear long trousers not shorts, t-shirts instead of muscle shirts. At the very least knees and shoulders should be covered. Long flowing ankle-length skirts and loose fitting men's t-shirts are recommended clothing for women. A headscarf is not necessary, but useful to have when visiting Ortodox churches and mosques. Learning basic survival-level Arabic is very helpful.
As the area is volatile and subject to sudden political changes, it is essential to listen closely to the news before and during your trip. Read the travel warnings issued by your government carefully and heed them.
Most travelers from Western countries can get visa for Turkey, Egypt, Jordan and Israel at the airport or at the border. Syria requires travelers to apply beforehand at the embassy of their country of residence. Travelers from a country which does not have diplomatic relationship with Syria can reportedly get the visa at the Syrian border too, but there seems to be no certain rule about it.
One reliable alternative for securing a Syrian visa is to apply at the Syrian Embassy in Istanbul. Processing time was less than 8 hours, so it is possible to apply in the morning and return later in the afternoon to retrieve your passport.
Since Syria is technically still at war with Israel, any proof of a past or future visit to Israel will result in being denied entry to Syria, even with a valid visa. Thus people intending to visit Israel on their trip travel from Turkey to Egypt, not the other way around. It is possible to keep a visit to Israel out of your passport if you enter and leave Israel through the Allenby-King Hussein bridge border crossing and request the Israeli officials to stamp a piece of paper instead of your passport. But this method is not very reliable.
It is practically impossible or not practical to pre-order bus, train or plane tickets online as most ticketing in the Middle East is still done by hand. Travel agents in Istanbul's Sultanahmet area can be of help for some parts of the trip and it can be worthwhile to email a trustworthy agent for help and pay for your tickets with credit card. This is frequently done for flights within Turkey or originating in Turkey, bus tickets departing Istanbul on not-so-frequent routes and for train tickets to Syria.
Most people will fly into Istanbul. Istanbul is a popular destination within the European network of budget flights. Some travelers arrive by train, bus and ferry from Greece or Bulgaria. There is a weekly bus to and from Germany via Italy and Greece.
Most people go to the Syrian border by bus.
Border crossings: Mardin-Nusaybin-Kamışlı (railroad, currently open), Mardin-Nusaybin-Kamışlı (highway border crossing, currently open), Mardin-Şenyurt-Derbesiye (highway border crossing, currently closed), Şanlıurfa-Ceylanpınar-Ra’sal Ayn (used during religious festivals), Şanlıurfa-Akçakale-Tell Ağabeyyat (highway border crossing, currently open), Gaziantep-Karkamış-Carablus (highway border crossing, currently open), Gaziantep-Çobanbey-Akderun (railroad and highway border crossing, currently closed), Gaziantep-Islahiye-Ekbez (railroad, currently open), Kilis-Öncüpınar-El Selame (Azez) (highway border crossing, currently open), Hatay-Cilvegözü-Bab Al Hawva (highway border crossing, currently open), Hatay-Yayladağı-Kesep (highway border crossing, currently open).
Antakya-Aleppo is the crossing most frequently used by travelers. There are buses across the border.
Aside from the bus, there is also a train that runs into Syria once a week.
Take the bus.
The bus is useful within Jerusalem on all days except Sabbath; There's a relaxing and inexpensive bus ride to Eilat.
As the area is volatile and subject to sudden political changes, it is essential to listen closely to the news before and during your trip. Read the travel warnings issued by your government carefully and head them.
Less dangerous but far more annoying are the various touts.