By car, US-101 and I-280 run through the city. It is also connected to the East Bay via the San Mateo-Hayward Bay Bridge.
Most convenient way is by car. If you're using public transit, check out the trip planner on http://www.511.org.
Fatima Seafood, 1208 El Camino Real, (650) 554-1818 This restaurant is an excellent example of Chinese Muslim food. Their hand-cut noodles beat most Italian restaurants, and their tea-smoked duck and onion breads are worthwhile driving from San Francisco to experience.
Taquería Pancho Villa, 365 South B Street, (650) 343-4123. The line out the door should give a clue to the quality inside. Well-roasted meats, tacos and real Mexican food made to order, and inexpensive. Their horchata is good, but their smoothies are better (and made with fresh fruit.)
Sinbad, 150 East 4th Avenue, (650) 347-6060. Your first impression of the place will be: It's a Turkish grocery store. Your second impression will be: It's a Turkish grocery store with some pre-cooked food available. Your final impression should be: It's a Turkish grocery store with impressively good, inexpensive Turkish food. Although their kebob plates are good, get the stew of the day -- whatever it is, it will be tasty.
Ray's Tea Time, 138 E. Third Avenue, (650) 348-7233. The original Taiwanese Tapioca Tea house in San Mateo, and still one of the nicest. Although it doesn't have as many flavors as the Q-Cup next door or the other tapioca place three doors down, Ray's Tea Time is among the most relaxing, welcoming tea houses in the Bay Area. The place also holds classes and sells Chinese goods. Free wireless hotspot. http://www.raysteatime.com
San Mateo Marriott. Located at the corner of two major freeways, great if you're staying in San Mateo to get somewhere else. Nice lobby for hanging out and a 7-11 convenience store just 1 block away for those late night alcohol runs. Interesting pool and exercise room setup as well. Abundant parking, but you have to pay for it (and it's controlled with gates).
If you're trying to go north to San Francisco, head to the Millbrae BART station nearby.
If you've already visited San Francisco, you can drive east to the East Bay via the San Mateo-Hayward Bay Bridge or further south down US-101 to Silicon Valley.