When all rules of hygiene have been scrupulously applied, antibiotic prophylaxis (ABP) is the one remaining means of further reducing surgical site infection risk. Its efficacy in major orthopedic surgical procedures is proven. Guidelines for indications and ABP systemic administration have been long established and are able to address many questions. By extrapolation, the same protocols apply in closed fractures, whereas they are less certain in open fractures, where successive and still incomplete reassessments have been made. There are no specific ABP protocols in implant revision for mechanical or infectious causes or in high-grade open fractures, despite the high associated risk of surgical site infection. All means of prophylaxis need exploring in these contexts: various molecule combinations, and various local applications. Although ideas are by no means lacking, levels of evidence are low or undetermined. Awaiting more objective data, the focus has to be on the quality of implementation. It is easy enough to conceive of ABP in terms of the tissue pharmacokinetics of the antibiotic(s), but real-life implementation is a real organizational challenge. Optimizing practices in clearly defined indications is still the prime objective for surgical ABP.