Most aquatic habitats are temporally dynamic, and selection has favored diverse strategies to persist in the face of fluctuating environmental conditions. Isolated wetlands in the southeastern United States harbor high diversities of aquatic and semi-aquatic organisms. However, drought may render these wetlands temporarily unsuitable for many species, sometimes for years at a time. We studied the movement patterns and demography of seven species of semi-aquatic snakes at Ellenton Bay, an isolated 10-ha freshwater wetland in the Upper Coastal Plain of South Carolina, following complete drying of the bay during a drought from 2000 to 2003. Behavioral and population responses varied markedly among species. Cottonmouths (Agkistrodon piscivorus) migrated to and from the wetland annually, fared well, and reproduced during the drought. Banded watersnakes (Nerodia fasciata) suffered a dramatic population decline and apparently did not reproduce, while eastern green watersnakes (N. floridana) were locally extirpated. Black swamp snakes (Seminatrix pygaea) aestivated within the wetland and were less affected by the drought than Nerodia. Interspecific differences in response to drought demonstrate that conservation measures may affect species differently and highlight the importance of terrestrial habitat around wetlands for semi-aquatic reptiles.