We stayed at the Radisson on Fisherman's Wharf and found this to be a great choice because they have an exit right out to Fisherman's Wharf, right across from Boudin's. If you have never heard of Boudin's it is an A-Mazing restaurant for their delicious clam chowder in a fresh sourdough bread. This location is also, for many, (but know your own limits) a perfect walking distance to the cable cars on the wharf and down the street from Pier 39. The hop-on-and-off bus also comes right to their front door. For wheelchairs, we found that it worked well for a quick exit but make sure you stay on the ground floor for better access.
In a quick weekend, we were able to walk over to the Red & White fleet and jump on an audio boat tour around the Golden Gate Bridge and Alcatraz Island. We enjoyed a meal on the wharf, dined on fresh seafood right from the vendors, walked around Pier 39 for shopping and lunch, hit up Ghirardelli for a chocolate sundae, and had a lovely anniversary dinner for my in-laws at Scomas. If you take the Hyde-Powell Cable car, you can also get off on Lombard St. (The crooked street) and walk down.
There are many car transportation companies that will take you back and forth from the airport and we were quoted $59 for each way (4 people). If that seems high, remember that everywhere charges for parking, not including the rental car rate and gas. Our hotel charged $45 a night to park and the Pier 39 is $8.00 an hour.