Prosthetic joint replacement is increasingly used to alleviate pain and increase mobility. Bone and joint infections remain a therapeutic dilemma for healthcare providers in all fields. Antimicrobial agents combined with appropriate surgical techniques play a vital role in eradicating infections associated with prosthetic joints. The question still remains whether monotherapy or combination therapy is effective in this situation because there is a paucity of well-defined comparative studies. We reviewed in vitro and in vivo studies evaluating the effectiveness of various antimicrobial agents either as single agents or in combination.