Lower extremity amputation is one of the worst complications of diabetes, as it usually has a life expectancy that is below that of most cancers. Four local biologic factors—ulcer, ischemia, neuropathy, and infection—have been shown to be related to amputation. These factors interact with one another, such that neuropathy has been shown to cause ulcers and ischemia and to prevent the healing of ulcers. In addition, ischemia and neuropathy are independent risk factors for infection. More coordinated efforts are needed to create better grading schemes and therapeutic protocols.