Charcot neuroarthropathy (CN) is a devastating condition affecting the feet in patients with diabetes. The pathophysiology of (CN) is still incompletely understood, although main etiological components have been identified. The cornerstone of treatment of acute CN is immediate effective offloading, typically with total contact casting, and reduction in weight-bearing. The main current targets of pharmacological intervention are the inhibition of excess osteoclast activation and suppression of an excess pro-inflammatory cytokine response. Anti-resorption therapy, especially with bisphosphonates, has been used in randomized trials. The trials so far have demonstrated improved symptom control, a more rapid decline in foot temperature and a significant decrease in bone turnover markers. An understanding of the molecular pathways of bone resorption will help in the development of novel adjunctive pharmacological therapies which might further improve the outcome in patients with CN.