The foot of patients with diabetes mellitus is affected by several processes which not only contribute to the development and progression of infection but on occasion alter the appearance of the foot in ways, which may obscure the clinical features of local infection. Neuropathy involving the motor fibers supplying muscles of the foot causes asymmetric muscle weakness, atrophy, and paresis which in turn result in foot deformities and maldistribution of weight (or pressure) on the foot surface. Dysfunction of the sensory fibers supplying the skin and deeper structural elements of the foot allows minor and major injury to these tissues to proceed without appreciation by the patient. As a result of neuropathy, the foot may be dramatically deformed, ulcerate in areas of unperceived trauma (mal perforans), and on occasion be warm and hyperemic in response to deep structural injury (acute Charcot’s disease). This warmth and hyperemia may be misinterpreted as cellulitis and ulceration, whereas a major portal of entry for infection may be uninfected. In the patient with diabetes, peripheral neuropathy may develop in isolation or commonly in parallel with atherosclerotic peripheral vascular disease. The latter involves major inflow vessels to the lower extremity but commonly is associated with occlusive lesions of the tibial and peroneal arteries between the knee and ankle. The resulting arterial insufficiency can alter the appearance of the foot and obscure infection. Rubor may reflect vascular insufficiency rather than inflammation and conversely pallor may mute the erythema of acute infection. Gangrene and necrosis may be primarily ischemic or may reflect accelerated ischemia in the setting of infection. In sum, the diagnosis of infection involving the foot in patients with diabetes requires a careful detailed examination of the lower extremity and its blood supply.