Bacterial skin and soft tissue infections are abundant worldwide and many are caused by Staphylococcus aureus. Indeed, S. aureus is the leading cause of skin and soft tissue infections in the USA. Here, we describe a mouse model of skin and soft tissue infection induced by subcutaneous inoculation of S. aureus. This animal model can be used to investigate a number of factors related to the pathogenesis of skin and soft tissue infections, including strain virulence and the contribution of specific bacterial molecules to disease, and it can be employed to test the potential effectiveness of antibiotic therapies or vaccine candidates.