The worst manifestation of neuro-osteoarthropathy of the pain-insensitive foot is the Charcot foot with its devastating osteoarticular destructions and irreversible deformities. New diagnostic tools such as MRI have revealed that mechanical injury and overuse is the origin of the condition. Traditionally, only feet with bone and joint damage apparent on plain radiographs (fracture and dislocation injuries) have undergone nonoperative treatment with off-loading and immobilization; however, treating painless, seemingly asymptomatic nonfracture injuries (bone bruise or bone marrow edema) with off-loading and immobilization has proven highly effective in preventing the Charcot foot. Whether pharmaceutical treatment has a role in terms of prevention or healing of osteoarticular destructions remains to be demonstrated.