The studies discussed here have shown a fairly consistent relationship between the effects of drugs on biogenic amines, particularly norepinephrine, and affective or behavioral states. Those drugs which cause depletion and inactivation of norepinephrine centrally produce sedation or depression, while drugs which increase or potentiate brain norepinephrine are associated with behavioral stimulation or excitement and generally have an antidepressant effect in man (Table 1). From these findings, a number of investigators have formulated the concept, designated the catecholamine hypothesis of affective disorders (6), that some, if not all, depressions may be associated with a relative deficiency of norepinephrine at functionally important adrenergic receptor sites in the brain, whereas elations may be associated with an excess of such amines. It is not possible either to confirm or to reject this hypothesis on the basis of currently available clinical data. Although there does appear to be a fairly consistent relationship between the effects of pharmacological agents on norepinephrine metabolism and on affective state, a rigorous extrapolation from pharmacological studies to pathophysiology cannot be made. Confirmation of this hypothesis must ultimately depend upon direct demonstration of the biochemical abnormality in the naturally occurring illness. It should be emphasized, however, that the demonstration of such a biochemical abnormality would not necessarily imply a genetic or constitutional, rather than an environmental or psychological, etiology of depression. Whereas specific genetic factors may be of importance in the etiology of some, and possibly all, depressions, it is equally conceivable that early experiences of the infant or child may cause enduring biochemical changes and that these may predispose some individuals to depressions in adulthood. It is not likely that changes in the metabolism of the biogenic amines alone will account for the complex phenomena of normal or pathological affect. Whereas the effects of these amines at particular sites in the brain may be of crucial importance in the regulation of affect, any comprehensive formulation of the physiology of affective state will have to include many other concomitant biochemical, physiological, and psychological factors. Although in this review of the relationship of biogenic amines to affective state relatively little has been said concerning the intricate set of environmental and psychological determinants of emotion, the importance of these factors must be stressed. The normally occurring alterations in affective state induced by environmental events is well known to all, from personal experience. The interactions between such environmental determinants of affect, various physiological factors, and the complexity of psychological determinants, including cognitive factors derived from the individual's remote and immediate past experiences, have received only limited study under adequately controlled conditions. It may be anticipated, however, that this will prove to be a particularly fruitful area for future research, for only within such a multifactorial framework may one expect to understand fully the relationship of the biogenic amines to emotional state.