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Buffalo is best seen by driving. The downtown area has plenty of one way streets, but is laid out in a grid format (designed by the same folks as Washington DC), so even if you miss a turn, you don't have to go particularly far out of your way to find anything.
The major highways* are the 290 and 190, Interstate 90, the 198 (The Scajaqueda) and the 33 which takes you either downtown or to/from the airport. A traffic jam also means very little, usually meaning that vehicles are SLOWED down, instead of sitting still.
For public transportation, the NFTA has a bus and light rail system that covers a good portion of the urbanized areas of Erie and Niagara counties. In the city of Buffalo, many of the major bus routes operate approximately every 15-20 minutes during the day, and from 30-60 minutes apart in the evenings. It's best to check the NFTA website to get specific times for the buses, and their use of Google's trip planner can save a lot of headache of looking at schedules you may not be familiar with. In addition, the Metro Rail system opens as early as 6:00am weekdays, and runs until midnight, with slightly later starting times on weekends. Most important lines connect with the Metro Rail system at at least on the 14 stations along the line.
The best deal for visitors is to purchase a day pass for $4.00, which allows UNLIMITED access to the entire bus and rail system during each day. Bus drivers and ticket vending machines at stations can distribute tickets easily. Keep in mind, if paying on each trip, the fare is $1.75, and can be paid for by the third vehicle you board.
*The Greater Buffalo Area's highway system is designed as several big circles. The 290 (which can take you to Grand Island, Niagara Falls, etc.) loops around, connecting to the 190 again, which connects to the 90, which connects to the 33 which eventually becomes the 198. It sounds confusing, but it essentially is pretty easy to make your way around the area.
Parking in and around Buffalo can be very difficult. If you are coming from out of town, understanding the different time restrictions and laws involving street parking can be confusing and potentially costly (being towed). The best bet is to utilize parking garages and lots in the area. Parking Panda allows you to plan your parking ahead of time. You can search for where you want to park near and locate garages in the area. Their site will give you prices for the day(s) you want to park and will even tell you how far away you're parking from your desired location.