Charcot neuroarthropathy is a devastating condition that places patients at risk for poor outcomes. Although the condition was first described in 1703, knowledge of the causative agent(s) has yet to be fully understood. Recent advances in genetic research have helped to identify potential mechanisms and pathways for the enigmatic destruction and deformities that are often associated with the condition; however, alternative pathways have been proposed. For the purpose of this discussion, we will discuss the human leukocyte antigen, which is one of the most researched contributors to autoimmune pathology and, more recently, has been linked to diabetic complications.