The pathophysiology, microbiology, and treatment of diabetic foot infections are reviewed. Patients with diabetes mellitus are at risk for developing infections of the lower extremity because of physiological and anatomical changes. The treatment must be aggressive to prevent systemic complications and recurrence. A combination of pathogens is likely to be found at the site of infection, including gram-negative and gram-positive aerobes as well as anaerobes. If preventive and nonpharmacologic treatment methods are not successful, systemic antimicrobial therapy is indicated. The appropriate agent for empirical therapy is chosen on the basis of the patient's medical history and clinical status with consideration to cost and administration issues. Until a specific organism is identified, a single broad-spectrum agent is administered. The duration of i.v. therapy and appropriate role for oral administration is based upon clinical response. Home infusion therapy is an option for medically stable patients. A single, broad-spectrum, i.v. antimicrobial is usually the best choice for empirical treatment of diabetic foot infection. The regimen is then tailored on the basis of the clinical response and culture and susceptibility test results. Aggressive pharmacologic and nonpharmacologic treatment is needed to avoid possible gangrene and loss of limb.