Neurotrophins and other growth factors have been advanced as critical modulators of depressive behavior. Support for this model is based on analyses of knockout and transgenic mouse models, human genetic studies, and screens for gene products that are regulated by depressive behavior and/or antidepressants. Even subtle alteration in the regulated secretion of brain-derived neurotrophic factor (BDNF), for example, due to a single nucleotide polymorphism (SNP)-encoded Val-Met substitution in proBDNF that affects processing and sorting, impacts behavior and cognition. Alterations in growth factor expression result in changes in neurogenesis as well as structural changes in neuronal cytoarchitecture, including effects on dendritic length and spine density, in the hippocampus, nucleus accumbens, and prefrontal cortex. These changes have the potential to impact the plasticity and stability of synapses in the CNS, and the complex brain circuitry that regulates behavior. Here we review the role that neurotrophins play in the modulation of depressive behavior, and the downstream signaling targets they regulate that potentially mediate these behavioral pro-depressant and antidepressant effects