Proceeding from recent evidence about the mechanism of action of lithium and of the novel antidepressant rolipram, it is proposed that functional disturbances in intraneuronal signal transmission distal to the receptors of classic neurotransmitters (first messengers) play a role in the etiology of affective disorders. The second-messenger dysbalance hypothesis suggests that affective disorders are caused by the functional dysbalance of the two major intraneuronal signal-amplification systems (the adenylate-cyclase and the phospholipase-C system), with depression resulting from hypofunction of cyclic adenosine-3',5'-monophosphate-mediated effector cell responses together with an absolute or relative dominance of the inositoltriphosphate/diacylglycerol-mediated responses, and mania resulting from the converse. The usefulness of this hypothesis is discussed with respect to (a) the mechanism of action of current therapeutics and (b) the development of novel therapeutic approaches.