Vibrio vulnificus is an opportunistic pathogen of humans that has the capability of causing rare, yet devastating disease. The bacteria are naturally present in estuarine environments and frequently contaminate seafoods. Within days of consuming uncooked, contaminated seafood, predisposed individuals can succumb to sepsis. Additionally, in otherwise healthy people, V. vulnificus causes wound infection that can require amputation or lead to sepsis. These diseases share the characteristics that the bacteria multiply extremely rapidly in host tissues and cause extensive damage. Despite the analysis of virulence for over 20 years using a combination of animal and cell culture models, surprisingly little is known about the mechanisms by which V. vulnificus causes disease. This is in part because of differences observed using animal models that involve infection with bacteria versus injection of toxins. However, the increasing use of genetic analysis coupled with detailed animal models is revealing new insight into the pathogenesis of V. vulnificus disease.