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San Francisco Anniversary Trip

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My wife are looking into visiting San Francisco, for the first time, for our 19th anniversary in March, 2014. We're fairly well traveled (I know, how have we not been to San Fran??) and in our late 30s. We like to blend into a neighborhood, as we've done in Rome, New York, etc., and thus like apartment rentals over hotels. We usually use vrbo.com or homeaway.com for rentals. We're both fit and enjoy walking whenever possible. A couple of specific questions:

1. What neighborhood(s) would you recommend? We love good food, wine, art, history, etc. Touristy is not really our thing.

2. What are the can't miss attractions, restaurants?

Thanks for any help Fodorites!

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