BACKGROUND: Surgical site infections (SSI), whether they be incisional or deep, can entail major morbidity and death to patients and additional cost to the healthcare system. A significant amount of effort has gone into optimizing the surgical patient and the operating room environment to reduce SSI. METHODS: Relevant guidelines and literature were reviewed. RESULTS: The modern practice of surgical antisepsis involves the employment of strict sterile techniques inside the operating room. Extensive guidelines are available regarding the proper operating room antisepsis as well as pre-operative preparation. The use of pre-operative antimicrobial prophylaxis has become increasingly prevalent, which also presents the challenge of opportunistic and nosocomial infections. Ongoing investigative efforts have brought about a greater appreciation of the surgical patient's endogenous microflora, use of non-bactericidal small molecules, and pre-operative microbial screening. CONCLUSIONS: Systematic protocols exist for optimizing the surgical sterility of the operating room to prevent SSIs. Ongoing research efforts aim to improve the precision of peri-operative antisepsis measures and personalize these measures to tailor the patient's unique microbial environment.