I read the article Touring San Diego - on the run in the travel section of the Seattle Times this morning. It details a reporter's experience with Jennifer Hughes of City Running Tours. The company does customized tours of San Diego for runners. Your guide offers information on the sights like any other tour guide, except you are both running along the streets rather than riding around on a bus.
I have heard from multiple sources that running is a great way to see a new city. You tend to take in your surroundings better than you do driving in traffic. It is also easier to set your own pace, linger at spots that interest you, and see things from a different perspective. The company takes reservations at www.zerve.com/cityrun which also features running tour companies in New York, D.C., Chicago and Charleston.
I think a bicycle tour of a new city would be another great experience. Of course it is easier to pack running shoes than a bicycle for your next trip.