Diabetic foot infections frequently cause morbidity, hospitalization, and amputations. Gram-positive cocci, especially staphylococci and also streptococci, are the predominant pathogens. Chronic or previously treated wounds often yield several microbes on culture, including gram-negative bacilli and anaerobes. Optimal culture specimens are wound tissue taken after debridement. Infection of a wound is defined clinically by the presence of purulent discharge or inflammation; systemic signs and symptoms are often lacking. Only infected wounds require antibiotic therapy, and the agents, route, and duration are predicated on the severity of infection. Mild to moderate infections can usually be treated in the outpatient setting with oral agents; severe infections require hospitalization and parenteral therapy. Empirical therapy must cover gram-positive cocci and should be broad spectrum for severe infections. Definitive therapy depends on culture results and the clinical response. Bone infection is particularly difficult to treat and often requires surgery. Several adjuvant agents may be beneficial in some cases.