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.  The "subway" system really only serves the UB North Campus to downtown, but can be great for getting to events at HSBC Arena, the Convention Center, or Pilot Field.

*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.