Although antidepressants have been used clinically for more than 50 years, no consensus has been reached concerning their precise molecular mechanism of action. Functional genomics is a powerful tool that can be used to identify genes affected by antidepressants or by other effective therapeutic manipulations. Using this tool we have previously identified more than 300 cDNA fragments as antidepressant related genes and from these, original cDNA microarrays were developed. Some of these candidate genes may encode common functional molecules induced by chronic antidepressant treatment. Defining the roles of these genes in drug-induced neural plasticity is likely to transform the course of research on the biological basis of depression. Such detailed knowledge will have profound effects on the diagnosis, prevention, and treatment of depression. Novel biological approaches beyond the "monoamine hypothesis" are expected to evoke paradigm shifts in the future of depression research.