There are several lengthy but highly informative wine & food recommendation threads on the first few pages of this forum and I found the FAQ sticky threads very useful when I planned my trip last June.

I'd echo Hiddy's Colonia Del Sacramento recommendation as I did the trip, though stayed a night rather than doing it as a day trip and I appreciated the extra time to wander this historic gem of a town.

There is so much to experience but I'd add my vote for seeing the city from a different perspective with a bicycle tour. The one I took left from Plaza San Martin and took in Puerto Madero, Ecologic Reserve, 'Costanera Sur', La Boca, San Telmo and Plaza de Mayo Square and was around 3 or 4 hours with a stop to wander along a bustling Caminito in La Boca. In good weather with a pleasant guide it can be a great way to see larger parts of the city than on foot and I really enjoyed my tour, especially since I was the only one on it so got a private tour.

Enjoy your visit, though after making it you'll almost definately reconsider whether it indeed will be your first and only trip. Heck, I'm already planning my next visit and plan to extend to see more of Uruguay this time.