The leading theory on the pathophysiology of tardive dyskinesia (TD) is that chronic treatment with dopamine receptor-blocking agents (DRBAs) causes a “supersensitivity” of dopamine receptors in the dorsal striatum. Researchers have begun investigating beyond the supersensitization theory. Chronic DRBA treatment may contribute to oxidative stress caused by other mechanisms, and it is possible that damage to interneurons may be involved. The notion of genetic susceptibility when it comes to a diagnosis of TD after treatment with antipsychotics is discussed.