Periprosthetic infection (PI) is a serious complication of total joint arthroplasty with high rates of associated morbidity, and a growing body of data suggests that bacterial biofilms are the underlying cause. Within a biofilm, bacteria display a ≥1,000-fold tolerance to antibiotics than their planktonic counterparts and significant resistance to innate and adaptive host immunity. Moreover, biofilms associated with orthopedic hardware are typically difficult to culture using conventional clinical microbiological methods, and the lack of a definitive diagnosis may result in an underestimate of infection rates. Consequently, the underlying infection is difficult to diagnose and treat, and often the only effective intervention is the twin strategy of thorough debridement and prostheses removal.