Catatonia has been rediscovered over the last 2 decades as a unique syndrome that consists of specific motor signs with a characteristic and uniform response to benzodiazepines and electroconvulsive therapy. Further inquiry into its developmental, environmental, psychological, and biological underpinnings is warranted. In this review, medical catatonia models of motor circuitry dysfunction, abnormal neurotransmitters, epilepsy, genetic risk factors, endocrine dysfunction, and immune abnormalities are discussed. Developmental, environmental, and psychological risk factors for catatonia are currently unknown. The following hypotheses need to be tested: neuroleptic malignant syndrome is a drug-induced form of malignant catatonia; Prader-Willi syndrome is a clinical GABAergic genetic-endocrine model of catatonia; Kleine-Levin syndrome represents a periodic form of adolescent catatonia; and anti-N-methyl-d-aspartate receptor encephalitis is an autoimmune type of catatonia. Copyright © 2010 by Lippincott Williams & Wilkins.