Charcot arthropathy of the foot and ankle is a severe complication of peripheral neuropathy and is most commonly seen in the developed world in association with diabetes mellitus. Correct diagnosis and differentiation from osteomyelitis of the foot and ankle are critical to guide treatment. It can exist concomitantly with osteomyelitis, typically in the setting of an advanced midfoot ulcer. Simple plain radiographs and contrasted MRI studies often yield inconclusive or confusing data. Correct use of imaging studies and a clinical algorithm can be effective tools to help make accurate and early diagnoses and guide clinical interventions for these conditions.