Diabetes mellitus is the leading cause of non-traumatic amputations worldwide. Ulcer of the diabetic foot is one of the most prevalent lesions of diabetic patients and it occurs in the natural evolution of the disease as a tardive complication. Neuropathy is the main determinant of foot ulcer. A key role is played by the loss of sensitive nerves, which prove to be a protective barrier against high pressure applied otherwise on the foot. The morphopathological characteristics of neuropathic lesions in patients with diabetes show important improvement associated with the pressure relieving treatment strategies. Therefore, pressure seems to impose a continuous mechanical stress on the wounded foot and it also sustains a chronic inflammatory condition, which slows down the healing process. Atherosclerosis is an imminent process to every person, nonetheless patients with diabetes mellitus have this process highly accelerated and more diffuse. One of the main characteristics of macrovascular lesions in diabetes is Mönckeberg's medial calcific sclerosis, calcification of the muscular layer, which clinically translates into an ankle-brachial index of 1 or above. Diabetes affects not only the large vessels, but it also produces microvascular lesions, which in time leads to diseases like retinopathy or nephropathy. Osteomyelitis is very common in the diabetic foot infections and the medical treatments are not satisfying. It is also believed to be a consequence of peripheral neuropathy that diabetes comes with. Osteomyelitis plays an important role in the prevalence of amputations in patients with diabetes. Obtaining clean, infection free margins is the most important goal, because residual osteomyelitis is a strong predictor of clinical failure and comes with many postoperative complications, even the necessity to operate again or have a major amputation later in evolution.