Recent evidence now suggests the involvement of the fibroblast growth factor (FGF) system in mood disorders. Specifically, several members of the FGF family have been shown to be dysregulated in individuals with major depression. In this review, we will introduce the FGF system in terms of structure and function during development, in adulthood, and in various regions and cell types. We will also review the FGF system as a mediator of neural plasticity. Furthermore, this review will summarize animal as well as human studies. The majority of animal studies have focused on stress, environmental enrichment, pharmacological manipulations, and the hippocampus. By contrast, human studies have focused on volumetric measurements, antidepressant literature, and, most recently, post-mortem microarray experiments. In summary, a reduced tone in the FGF system might alter brain development or remodeling and result in a predisposition or vulnerability to mood disorders, including major depression.