The characterization of depression as a treatable disease has led to very significant research aimed at understanding disease mechanisms and treatments. Antidepressant therapy, employing chemical and non-chemical antidepressants are quite successful in treatment of the disorder although their mechanism of action is not well understood. Basic research with rodent models is providing vital evidence concerning the molecules and mechanisms involved in antidepressant action. The regulation of neurotrophic and growth factors observed after antidepressant administration is seen as playing an important role in modulating the therapeutic effects of antidepressants. Recently, adult neurogenesis or the birth of new neurons has emerged as a physiological phenomenon necessary for the behavioral response of antidepressant treatment. Equally interesting are correlative associations between neurogenesis and angiogenesis or the birth of new vasculature. Growth factors such as brain derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) play vital roles in both these phenomena making the interplay of neurogenesis and angiogenesis an exciting avenue of brain research. This review will focus on the research that has led us to this current understanding of antidepressant action in context with the pathophysiology of depression using examples from basic, preclinical and clinical investigations.