The contribution of bacterial proteases to virulence has been relatively understudied. It is a simple matter to argue that bacterial proteases have the potential to destroy the structural and functional proteins that constitute host tissues as well as to destroy proteins important in host defense. Systematically demonstrating that such interactions occur during disease pathogenesis is more difficult, although a few studies have suggested that the ability of a pathogen to use proteases to cross proteinaceous barriers within the host contributes to bacterial virulence. This manuscript reviews concepts of bacterial virulence. Next, it describes how the host regulates the activities of its own proteases to maintain a state of health, and examines evidence suggesting that dysregulation of host proteases results in disease. Finally, evidence supporting a role for endogenous microbial proteases or acquisition of host proteases by microbes as virulence determinants is discussed as are suggestions for future directions for research in this area.