The cholinergic-adrenergic balance hypothesis of affective disorders suggests that, in the areas of the brain that regulate mood, depression may represent a relative predominance of central cholinergic tone over adrenergic tone and that mania may represent the converse. Currently, converging lines of investigation from a number of independent groups suggest that affective disorder patients may have a central cholinergic receptor hypersensitivity that induces a vulnerability to affective and neuroendocrine disturbances. This article reviews the evidence for cholinergic mechanisms in the regulation of affective state and describes current research strategies using centrally active cholinomimetic agents to explore disturbances in affective disorder subjects.