Substance P (NK1 receptor) antagonists (SPAs) are currently the best validated and clinically most advanced novel approach to treating major depressive disorder (MDD), and several compounds are in advanced clinical development. Three years since the discovery of the antidepressant efficacy of MK-869 (Merck & Co Inc), the first in a new class of drugs that act by selectively blocking the actions of substance P, the principle that blocking the NK1 receptor can alleviate major depression has recently been replicated in a placebo-controlled, blinded study. SPAs are active in a range of preclinical assays that detect clinically used antidepressant drugs, but they have a pharmacological profile that is distinct from established drugs. There is preliminary evidence that substance P and NK1 receptor density may be altered in MDD, suggesting a possible link between substance P and depressive pathophysiology. Studies in animals indicate that the psychotherapeutic effects of SPAs may be mediated at least partly through stimulation of hippocampal neurogenesis, by direct blockade of NK1 receptors in the amygdala and its associated output projections, and also via interactions with monoamines. Additional studies are needed to explore these hypothesesfurther.