This article will heuristically overview some of the more recent conceptualizations of the pathogenesis and pathophysiology of major depression as well as the functional changes in the central nervous system accompanying its successful pharmacotherapy. The neuropharmacology of affective disorders is a rapidly advancing field of scientific interest with significant complexity and numerous apparently contradictory findings. Within the space limitations of this article, some of the relevant newer conceptualizations of the pathophysiology and treatment of affective disorders will be summarized. Major concepts to be presented include the following: (1) the pathogenesis of affective illness may be conceptualized as an interaction between early and current life stressors and genetic vulnerability; (2) affective illness has been increasingly conceptualized as a potentially chronic progressive illness rather than an intermittent illness with full recovery between episodes; (3) affective illness, including its various stages, may be readily documented and monitored through changes in functional brain imaging; and (4) due to advances in molecular biology technology, there has been increasing evidence documenting changes in genetic activity involved in the pathogenesis of affective disorders from environmental stressors and/or from inherited genetic alterations and of the reversal of these changes accompanying successful pharmacotherapy.