The problem of prophylaxis in orthopedic implant surgery will become increasingly important and complex as the population ages and requires more arthroplasty procedures, and the prevalence of antimicrobial-resistant bacteria meanwhile also continues to rise. Energy spent preventing prosthetic joint infection is more effective than that expended in treating the infection of a prosthetic joint, once established. Preventive measures encompass a wide array of variables related to host response, wound environment, and microorganisms. Prophylaxis should address these areas in the preoperative, intraoperative, and postoperative periods. Antimicrobial prophylaxis remains the single most effective method of reducing the prevalence of infection after total joint arthroplasty. In the postoperative period, prophylaxis aims to protect the prosthetic joint against hematogenous seeding from oral, urologic, skin, or gastrointestinal sources. Currently, dental and urologic advisory statements provide recommendations for antimicrobial prophylaxis for high-risk patients with total joint arthroplasty undergoing high-risk procedures. Close collaboration between the orthopedic surgeon, urologist, or dentist and the infectious disease specialist is crucial for providing recommendations regarding prophylaxis in special circumstances. In these particular circumstances, individual decisions should be made based on clinical judgment.