Prosthetic implantation is rising in popularity in the United States, and use of prostheses will only continue to increase with the aging of the Baby Boomer generation. A concurrent rise in the number of infections of these implants is also being seen. Prosthetic implant infection (PII) can be caused by direct inoculation of bacteria to the implant or by seeding from the blood (hematogenous). Because the implant is quickly coated by host connective tissue upon implantation, bacteria such as the staphylococcal species S. aureus and S. epidermidis are able to readily gain a foothold in the host. S. aureus is able to quickly develop antibiotic resistance and methicillin-resistant strains (MRSA) are considered endemic in hospitals. This bacterium features a myriad of virulence factors that allow it to colonize and damage the host, as well as avoid the host immune response. These virulence factors are largely regulated through population-based quorum sensing via the agr system. S. aureus is also able to form biofilms, microbial communities encased in a polysaccharide matrix, which allows the bacteria within to persist in the face of antimicrobial therapies and the host response. Diagnosis of PII is difficult with many false results and confusion with aseptic loosening of the implant. Because of ineffective means of diagnosis, combined with S. aureus’ high incidence of antibiotic resistance and its ability to evade both antibiotics and the host response through biofilm formation, treatment for PII is often inadequate and infection can become chronic. Therefore, PII has a high rate of morbidity and mortality for patients, as well as an extreme economic burden on the US healthcare system.