Brain-derived neurotrophic factor (BDNF) is a member of the structurally and functionally homologous neurotrophin family. It is the most widely distributed trophic factor in the brain, and participates in neuronal growth, maintenance, and use-dependent plasticity mechanisms such as long-term potentiation and learning. There are several lines of evidence supporting a role for BDNF in the treatment of depression. This paper reviews the neurotrophin hypothesis of antidepressant action, and examines our current understanding of activity-dependent mechanisms of BDNF expression and function in limbic regions of the brain. Our discussion starts with the original observations of monoaminergic neurotransmitter dysfunction that served as the basis for early antidepressant drug development, and outlines evidence for neurodegeneration and functional deficits existing with chronic stress and depression. We continue with evidence that enhancement in neurotrophic support and associated augmentation in synaptic plasticity and function may form the basis for antidepressant efficacy, and serve as a current and future focus in the quest for more rapid-acting and effective medication treatments. Finally, we follow the current search for the intracellular mechanisms of antidepressant interventions that may bring the monoaminergic and neurotrophic hypotheses together, and help us to more fully understand the roles of both neurotransmitter and growth factor. Principal challenges to the neurotrophin hypothesis, and inconsistencies between clinical and preclinical research results, are also pointed out, as these also guide future experiments that will refine our understanding of treatment mechanisms.