Research on Substance P (SP) has, until recently, focused on its role in pain and inflammation. However, a report that NK1 receptor antagonists have utility in the treatment of depression has stimulated research into the function of SP and the NK1 receptor in anxiety and depression. The distribution of SP and the NK1 receptor in brain areas implicated in anxiety and depression is initially reviewed. This is followed by evaluation of the preclinical data obtained for SP and NK1 receptor antagonists in behavioral models of depression as well as the phenotype of genetically modified animals lacking the genes encoding for the NK1 receptor or for SP. The weight of the evidence supports antidepressant and anxiolytic activity of NK1 receptor antagonists. However, many of the studies do not control for nonspecific effects of the compounds, and when enantiomers that lack activity at the NK1 receptor are included, the results, in some cases, suggest that blockade of NK1 receptors does not account for the observed behavioral activity. Finally, clinical studies in depressed patients assessing SP levels in plasma and cerebrospinal fluid as well as the effect of NK1 receptor antagonists are reviewed. The clinical studies are a mixture of positive, failed and negative studies on the antidepressant activity of NK1 receptor antagonists, not unlike the early clinical results obtained with selective serotonin reuptake inhibitors.