One approach to research into depressive illness includes a clinical pharmacotherapeutic tack such as the use of investigational drugs with defined pharmacological and biochemical activity. Using this research strategem, a variety of new compounds have been investigated in recent years all of which are unique chemically; all differ from the classic tricyclic-MAOI compounds. Animal pharmacology and neurochemical studies also show a profile which largely differs from the standard reference compounds. Their effects on central monoamine metabolism differ widely; some act pre- and others postsynaptically, some act by re-uptake inhibition, others by enhancing release, others are precursors, while still others are receptor agonists; some have no apparent central effect. The data, considered collectively and critically evaluated, suggest that many of the newer compounds used investigationally, because of their clinical efficacy, seriously question the involvement of monoamines as responsible for either the antidepressant effect of the standard psychotropic drugs or as etiopathogenic in the affective disorders. The classic animal screening profiles used for predicting antidepressant drug efficacy in man do not hold for many of these newer antidepressants. the animal-laboratory models need be revised and reoriented towards finding similar molecules that are devoid of the addling side effects and contraindications of the existing standard tricyclic-MAOI genre. The newer second generation antidepressants stand as a hallmark of progress in research and treatment with psychotropic drugs.