Neuropathic ulcerations and altered immune function place the diabetic patient at increased risk for polymicrobial osteomyelitis of the foot and ankle. The optimal method for evaluation and management of this difficult condition is controversial, and further studies are needed. Infected ulcers with exposed or palpable bone can be assumed to have underlying osteomyelitis. Although plain film should be ordered in each case, MRI is most often used for evaluation and surgical planning. Difficult cases, such as those associated with Charcot osteoarthropathy, may require labeled leukocyte scanning or bone biopsy to arrive at the diagnosis. A multidisciplinary team approach is best, allowing optimal treatment of all associated conditions that commonly affect patients with diabetes mellitus. Vascular evaluation and intervention are critical in the presence of vascular insufficiency or ischemia. Empiric, usually broad-spectrum antibiotics and meticulous local wound care may achieve remission of mild to moderately severe infections and should be included in all treatment regimens. Severe, infections, ischemia, or sepsis requires an aggressive surgical approach. Bone resection, correction of deformity, or amputation often are necessary and should be done with the goal of salvaging a functional foot.