Each year, 82,000 limb amputations are performed in patients with diabetes mellitus. The majority of these amputations could be avoided by following strict protocols. The collective experience treating patients with neuropathic diabetic foot ulcers of 4 major diabetic foot programs in the United States and Europe were analyzed. The following protocol has been developed for patients with diabetic foot ulcers: (1) measurement of the wound by planimetry; (2) optimal glucose control; (3) surgical debridement of all hyperkeratotic, infected, and nonviable tissue; (4) systemic antibiotics for deep infection, drainage, and cellulitis; (5) offloading; (6) moist-wound environment; and (7) treatment with growth factors and/or cellular therapy if the wound is not healing after 2 weeks with this protocol and a new epithelial layer is not forming. In addition, the pathogenesis of diabetic foot ulcers is discussed, as well as the associated costs and complications, including amputation. Debridement, wound-bed preparation, antibiotics, various types of dressings, biological therapies, growth factors, and offloading are described as treatment modalities for patients with diabetic foot ulcers. In diabetic foot ulcers, availability of the above modalities, in combination with early recognition and comprehensive treatment, ensure rapid healing and minimize morbidity, mortality, and costs, as well as eliminate amputation in the absence of ischemia and osteomyelitis.