Phenomenological and physiological variables demonstrate supersensitive changes to cholinergic challenge in affective disorder subjects. Theorists generally assume the primary defect is the postsynaptic muscarinic receptor. However, in addition to defectiveness or up-regulation of this receptor, the appearance of postsynaptic "cholinoceptor supersensitivity" can result from abnormal presynaptic mechanisms, membrane "pathology," derangement of intrasystolic mechanisms that amplify effects of receptor-agonist coupling, or aberrant cholinergic-monoaminergic interaction. This article discusses abnormalities of the postsynaptic receptor, regulation of postsynaptic receptor density, the presynaptic muscarinic receptor, and other mechanisms regulating the release of acetylcholine, membrane dynamics, and "cascade" mechanisms-specifically the phosphatidylinositol (PI) cycle, Ca2+ mobilization, and cyclic guanosine monophosphate (GMP) generation-as causes of cholinergic system "supersensitivity." It is suggested that an approach to the topic emphasizing site of abnormality will encourage greater clarity of thought in the study of the cholinergic component of the pathophysiology of affective illness.