Neuroleptic malignant syndrome is a rare and potentially lethal disorder associated with the use of antipsychotic medications. Heightened vigilance on the part of clinical providers has reduced morbidity and mortality caused by this disorder over the past decade, but there is still no consensus regarding its diagnosis, pathophysiology, or treatment. Efforts to demonstrate a direct link between neuroleptic malignant syndrome and malignant hyperthermia have been unsuccessful, indicating mutually distinct etiologies despite striking clinical similarities. This paper concisely reviews essential aspects of electromechanical transduction in muscle and nerve cells and current knowledge concerning the pathophysiology of malignant hyperthermia and neuroleptic malignant syndrome. Utilizing this conceptual framework, the author proposes that neuroleptic malignant syndrome may be caused by a spectrum of inherited defects in genes that are responsible for a variety of calcium regulatory proteins within sympathetic neurons or the higher order assemblies that regulate them. In this proposed model, neuroleptic malignant syndrome may be understood as a neurogenic form of malignant hyperthermia.