Success in the treatment of infected orthopedic prosthesis requires the best surgical approach in combination with prolonged optimum targeted antimicrobial therapy. In choosing the surgical option, one must consider the type of infection, condition of the bone stock and soft tissue, the virulence and antimicrobial susceptibility of the pathogen, the general health and projected longevity of the patient, and the experience of the surgeon. If surgery is not possible, an alternative is long-term oral antimicrobial suppression to maintain a functioning prosthesis. Treatment must be individualized for a specific infection in a specific patient.