There are so many hotels in San Diego. It really depends on what I will be doing in San Diego. Sometimes I attend a conference downtown. When this happens, I book a hotel as close to the Convention Center as I can so that I can walk to the conference.
For a family vacation, I like the Mission Bay area because it is centrally located near the freeways to get around to see the different attractions. If I'm interested in spending a few days relaxing on the beach, I book a hotel on the beach. It's pricey, but Pacific Terrace is one of my favorite beach hotels located right on the beach in Pacific Beach. The Hilton at Mission Bay is also quite nice. There are so many great choices!