The impacts of climate change on human health have been documented globally and in the United States. Numerous studies project greater morbidity and mortality as a result of extreme weather events and other climate-sensitive hazards. Public health impacts on the U.S. Gulf Coast may be severe as the region is expected to experience increases in extreme temperatures, sea level rise, and possibly fewer but more intense hurricanes. Through myriad pathways, climate change is likely to make the Gulf Coast less hospitable and more dangerous for its residents, and may prompt substantial migration from and into the region. Public health impacts may be further exacerbated by the concentration of people and infrastructure, as well as the region’s coastal geography. Vulnerable populations, including the very young, elderly, and socioeconomically disadvantaged may face particularly high threats to their health and well-being. This paper provides an overview of potential public health impacts of climate variability and change on the Gulf Coast, with a focus on the region’s unique vulnerabilities, and outlines recommendations for improving the region’s ability to minimize the impacts of climate-sensitive hazards. Public health adaptation aimed at improving individual, public health system, and infrastructure resilience is urgently needed to meet the challenges climate change may pose to the Gulf Coast in the coming decades.