Pedal infection in diabetic patients is both a common and potentially disastrous complication that can progress rapidly to irreversible septic gangrene necessitating amputation of the foot. The choice of optimal antibiotic therapy depends on an accurate assessment of sepsis severity, reliable microbiologic data, and consideration of host factors, such as renal and vascular impairment. Empiric broad-spectrum antibiotic regimens are generally preferred because of the polymicrobial nature of most pedal infections. Mild infections may be treated as an outpatient with oral antibiotics and close clinical review while moderate/severe (limb-threatening) and severe (life-threatening) infections require resection of necrotic tissue, parenteral broad-spectrum antibiotic therapy, and in some cases, lower limb revascularization once sepsis has been controlled. Pedal osteomyelitis frequently requires prolonged antibiotic therapy or resection of involved bone. In this article, treatment trials are reviewed and suitable antibiotic regimens commensurate with the severity of infection are proposed.