Treatment of infections associated with orthopedic devices usually requires appropriate surgical intervention combined with a prolonged course of antimicrobial therapy. The choice of optimal management depends on duration and pathogenesis of infection, stability of the implant, antimicrobial susceptibility of the pathogen and condition of the soft tissue. The role of rifampin in combination with quinolones, minocycline, co-trimoxazole or fusidic acid in the treatment of staphylococcal infections is outlined in this review. Increasing antimicrobial resistance requires the use of alternative agents, such as quinupristin-dalfopristin, linezolid and daptomycin, but results of clinical trials are limited. Finally, agents with a potential for treatment or prophylaxis of device-associated infections, such as novel rifamycin derivatives, and compounds acting on bacterial quorum-sensing mechanisms are presented in this review.