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This symposium offers the practicing clinician a general overview of ongoing research strategies exploring possible functional alterations in neurotransmitters, neuroreceptors, and regulatory neuropeptides in subjects with major affective disorders. Such alterations, if demonstrable, might provide new mechanistic insights into the pathophysiology of these illnesses and suggest novel therapeutic approaches to their pharmacological management. Rather than attempting to describe all neurobiological research strategies, we have selectively focused on strategies using specific pharmacological challenges attempting to perturb discrete central nervous system neurotransmitter pathways while recording the behavioral and neuroendocrine correlates of such manipulations. This introductory manuscript will describe the advantages as well as the limitations of such strategies and, in addition, will attempt to provide a general overview of neuroanatomical, neurochemical, and neuroendocrine mechanisms relevant to a conceptual understanding of the putative psychiatric relevance of such strategies.