I'm with jdarg. When we need a quick weekend getaway, this is where we go. We always start out at the Gibson (love their Bloody Marys). For food, we like Veranda's (for appetizers), Boss (for oysters), and Apalachicola Seafood Grill for their fried fish sandwich and chowder. I would like to get to Tamara's and the new Avenue Sea in the Gibson. My favorite shop is Avenue E...I could spend hours in there. For stylish clothes (and take home souvenirs), I visit the Grady Market. There is an awesome nautical shop that is always a treat....also a funky gift shop and bookstore that is just as fun to visit. I love just exploring the old buildings...shops or not.
The last time we visited, we stayed at the new Water Street Hotel which sits directly on the river. The rooms are actually like upscale condominiums with private huge screened porches, each with a fantastic view of the river. I could not believe how beautiful they were. It's also a marina, so you can dock your boat as well. Ask for room 310 (corner unit with the best views all around). The Consulate is another I 'd like to try (these luxury suites are located above the Grady Market with views of the river or garden)...BUT one cannot stay in Apalachicola without staying at the Gibson at least once. This place really gives you a good feel for the town. ;-)
The ONLY nightlife I know of is The Spoonbill, as someone else had mentioned.....all the locals come out for serious (and I mean serious) karaoke. It's always interesting.