Most antidepressants in use today are descendants of the monoamine oxidase inhibitor iproniazidand the tricyclic agent imipramine. These agents were both originally developed for other indicationsbut then were serendipitously determined to have antidepressant effects. Elucidation of the mechanismsof action of these first antidepressants, along with those of reserpine and amphetamine, led tothe monoamine theories of depression. Through the past several decades, approaches undertaken toclarify the roles of the neurotransmitters norepinephrine, dopamine, and serotonin in depression haveincluded animal studies, human biological and postmortem studies, inferences drawn from antidepressantdrug actions, and challenge or depletion studies; most recently, brain imaging studies haveproved to be especially informative. This research has identified novel potential targets, with the goalof developing new antidepressant drugs with better efficacy and faster onset of action than current”gold-standard” treatments.