We did a good fly-drive a few years back. Flew into San Francisco, spent three days there, then a leisurely drive down the Pacific Coast Highway (some of the most stunning scenery you'll ever see), stopping overnight in places like Carmel (Clint country!). Monterey, San Luis Obispo (nice town) and Santa Monica. Then inland to Lake Tahoe, stayed in a cabin there for three days — absolutely stunning, lots of outdoor activities, walking trails etc and on the Nevada side of Stateline, a mini-Vegas of casinos, clubs etc. Then a day in Yosemite (wish it could have been longer ) before returning to San Fran for the final three days. One of the best holidays I've ever had.
Ps we stayed in the Westin St Francis in Union Square. The Tenderloin is only a few blocks away and one afternoon I walked through it wearing a City shirt. Lots of down and outs and porno clubs and theatres, but nobody bothered me, though I'd be less confident at night.
Went bar hopping in the Mission one night. It was okay, seemed to be lots of converted industrial buildings. Can see how it could be shady in palces, though.
Apart from the usual tourist sports like Chinatown, Fisherman's Wharf and Alcatraz, just walking around San Francisco is like being on a movie set. It is crammed with hidden gem. If you go, try the hot pastrami sandwich on rye or Siberian black bread from David's Deli, just off Union Square. Amazing