Loss of pain perception is currently seen as a key factor in the development of diabetic foot ulcers. However, recent studies suggest that nerves play a central role in tissue homeostasis and can orchestrate complex reparative as well as destructive processes in the feet. Evidence is presented that suggests that denervation can result in altered capillary blood flow (in patients with type 2 diabetes), oxygen delivery, fluid filtration, and inflammatory responses. These processes could render the feet of diabetic patients with neuropathy more susceptible to tissue damage, infection and perhaps, in a subset of patients, to the development of acute Charcot neuro-osteoarthropathy (CN). Copyright © 2008 John Wiley & Sons, Ltd.