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.
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 (yes, you read that right: there's another tapioca drink place next door!), 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.