Infections of the foot in the person with diabetes are the result of a complex myriad of pathophysiologic alterations. Neuropathy, vascular disease, and host immune alterations all interact to present a fertile ground for significant microbiologic invasion. When infection occurs, it is commonly due to a mixed flora of aerobic and anaerobic organisms, although "pure" aerobic or anaerobic infections are sometimes seen. Treatment of these infections requires a broad approach, including surgery, local care, and antibiotics. Most often, treatment against aerobic and anaerobic pathogens will be necessary. These infections can be divided into two categories based on clinical appearance. Severe life- or limb-threatening infections can present with massive cellulitis of the foot and leg, high fever, significantly elevated white blood count, septicemia, and tissue gas. Appropriate antibiotics in this setting include either combination or single-agent therapy. Imipenem/cilastatin offers coverage of all usual pathogens along with potentially lower toxicity and lower cost than combinations. Combinations containing clindamycin and aztreonam or ciprofloxacin may be useful for patients allergic to beta-lactam antibiotics. Less severe infections can usually be treated with a single-agent antibiotic such as ticarcillin/clavulanic acid or ampicillin/sulbactam. Cephalosporins with anaerobic activity, including cefoxitin, cefotaxime, and ceftizoxime, can be used in areas where enterococci are not a major problem.