Substance P (SP) is an 11-amino acid neuropeptide of the tachykinin family that preferentially activates the neurokinin-1 receptor (NK1R). First isolated 85 years ago and sequenced 40 years later, SP has been extensively studied. Early studies identified a role for SP and the NK1R in contraction of intestinal smooth muscle, central pain processing, and neurogenic inflammation. An FDA-approved NK1R antagonist, aprepitant, is used clinically for the treatment of chemotherapy-induced nausea, as the NK1R influences the activity of the brain stem emesis centers. More recently, SP and the NK1R have gained attention for their role in complex psychiatric processes including stress, anxiety, and depression. However, clinical development of NK1R antagonists for these indications has so far been unsuccessful. Several preclinical studies have also demonstrated a role of the NK1R in drug taking and drug seeking, especially as it relates to escalated consumption and stress-elicited seeking. This line of research developed in parallel with findings supporting a role of corticotropin-releasing factor (CRF) in stress-induced drug seeking. Over this time, CRF arguably gained more attention as a target for development of addiction pharmacotherapies. However, this effort has not resulted in a viable drug for use in human populations. Given promising clinical findings for the efficacy of NK1R antagonists on craving in alcoholics, along with recent data suggesting that a number of negative results from NK1R trials were likely due to insufficient receptor occupancy, the NK1R merits being revisited as a target for the development of novel pharmacotherapeutics for addiction.