Surgical site infection (SSI) following orthopedic foot and ankle surgery is associated with morbidity, mortality, and cost to the healthcare system. The local anatomy and physiology predispose patients undergoing procedures to elevated risk. In particular, sterilizing of the webspaces, nailfolds, and subungual areas presents challenges, and the preferred skin antisepsis technique for foot and ankle procedures has not yet been defined. Skin antiseptic solutions (SASs) consist of 3 main categories: alcohol, chlorhexidine, and iodine-based solutions. This review of the literature supports a combined chlorhexidine and alcohol preparation technique; however, there are a number of studies that suggest otherwise. In addition, there is variable evidence for the use of alternatives to the standard soft sponge application technique, including immersion, bristled brush, and cotton gauze application. These alternatives may have a particular advantage in the forefoot. Most studies to date use growth from skin swab cultures after skin preparation as the primary outcome. Higher-level studies with large subject populations and more meaningful clinical outcomes will be required to solidify guidelines for preoperative skin antisepsis prior to foot and ankle procedures. Level of Evidence: Level V, expert opinion.