Stiff-Man syndrome (SMS) is a disorder of the CNS, characterized by rigidity of the body musculature, which has been hypothesized to result from an impairment of GABAergic neurotransmission. GABA is the main inhibitory neurotransmitter of the brain. It is also a putative signal molecule in the pancreas, where it is produced by beta cells (insulin-secreting cells)--the autoimmune target in insulin-dependent diabetes mellitus (IDDM). Autoantibodies to the GABA-synthesizing enzyme glutamic acid decarboxylase (GAD) have been found in SMS and in IDDM. This review summarizes evidence suggesting that SMS may be an autoimmune disease and discusses the possible significance of the autoimmune response to GAD in SMS and IDDM.