I live locally and only know hotels from their location and others' opinions on FlyerTalk. For me, a special location is a hotel on water. Let me give you some names and you can research further in the respective hotel forums.
Hilton Torrey Pines - on bluffs above ocean between UCSD campus and Del Mar
Cape Rey Carlsbad, on the southern end of the charming town of Carlsbad, across the road from the water.
Hyatt Huntington Beach - I have seen praise for this property over and over, but again, have no personal experience.
In San Diego, I'd consider Hyatt Mission Bay (near Sea World) and Park Hyatt Aviara in La Costa. I've stayed at the Andaz San Diego and don't like it. It's too noisy and on the weekends is a nightclub that happens to have some hotel rooms. Manchester Grand is massive, on the water by the convention center. It's easy walking to the Gaslamp District with its myriad of restaurants and Seaport Village.