Recent findings and recommendations on the use of antibiotics in surgery, both prophylactically and as therapy, suggest that adverse events associated with antibiotics remain a major cause of morbidity and mortality. Wound infection rates generally parallel the presence of one or more of three key risk factors; the overall medical condition of the patient, a prolonged operative time, and a contaminated or dirty operative field. The first choice of prophylactic drug should generally be a first- or second-generation cephalosporin, unless the patient is highly allergic to penicillin. Effective prophylaxis can almost always be achieved with a single dose of antibiotic, but the dose must be administered soon before the incision. New guidelines for the prevention of bacterial endocarditis have reduced both the types of cases that require prophylaxis, and the doses of antibiotic necessary to achieve prophylaxis. Some cases that required endocarditis prophylaxis previously no longer require prophylaxis. Rational antibiotic therapy demands rapid diagnosis and treatment. It is also crucial to distinguish among infection, contamination, and inflammation as soon as possible; contamination requires only a single dose of antibiotic, whereas sterile inflammation requires none at all. The choice of antibiotic for postoperative infection, including intra-abdominal infection, should consider the severity of illness and the risk of resistant bacteria. Failure to stratify for risk may prolong treatment unnecessarily, confound the interpretation of future studies, and increase the prevalence of bacterial resistance.