The extensive and ever-increasing use of long-term prosthetic devices has improved quality of life and survival for many patients. Prosthetic device-related infection occurs infrequently but is associated with significant morbidity and mortality. Management is challenging, often requiring prolonged antimicrobial therapy and surgical intervention. Better understanding of the interaction between microorganisms, devices, and the host should improve the ability to manage device-related infections. This article reviews recent advances in the diagnosis and treatment of infections associated with indwelling medical devices, highlighting those associated with prosthetic joints, cerebrospinal fluid shunts, and prosthetic heart valves.