Atherosclerotic peripheral vascular disease in patients with diabetes is a major factor in the progression of diabetic foot pathology. The rate of lower extremity amputation in the diabetic population is 15 times that seen in the nondiabetic population (1). A number of factors conspire in the patient with diabetes, each of which synergistically contributes to this extremely high amputation rate. Peripheral neuropathy, infection, microvascular changes, and macrovascular changes all have complex interplay. Peripheral neuropathy leads to structural and sensory changes within the foot, making the limb injury-prone. In addition, once it occurs, that injury is often not easily detectable and heals slowly if at all. Microvascular changes are nonocclusive changes in the microcirculation that lead to impairment of normal cellular exchange, again preventing easy healing. Infection in patients with diabetes can often be aggressive and polymicrobial. Macrovascular disease, atherosclerosis of the peripheral arteries, contributes to poor perfusion of the extremities. Although the underlying pathogenesis of atherosclerotic disease in patients with diabetes is similar to that noted in patients without diabetes, there are some significant differences. It is important to realize that the diabetic foot is more susceptible to moderate changes in perfusion than the nondiabetic foot, resulting in a greater sensitivity to atherosclerotic occlusive disease. Compounding this scenario is the fact that patients with diabetes are noted to have a fourfold increase in the prevalence of atherosclerosis as well as a propensity for accelerated atherosclerosis. This chapter will review the pathobiology and anatomic distribution of occlusive disease in the patient with diabetes, the usual clinical presentation of peripheral vascular disease, and the various diagnostic modalities useful in planning treatment. It will conclude with a diagnostic and treatment protocol that can be used in patients presenting with this multifactorial disease process.