The development of small-molecule antagonists of the substance P (SP)-preferring tachykinin NK1 receptor during the past decade represents an important opportunity to exploit these molecules as novel therapeutic agents. On the basis of its anatomical localization and function, SP has been implicated in diverse pathophysiologies; of these, diseases of the CNS have been examined in the greatest detail. Although SP is best known as a pain neurotransmitter, it also controls vomiting and various behavioural, neurochemical and cardiovascular responses to stress. Recent clinical trials have confirmed the efficacy of NK1 receptor antagonists to alleviate depression and emesis but, surprisingly, not pain. Thus, multiple clinical trials, targeted to appropriate patient populations, are necessary to define the therapeutic potential of novel neurotransmitter ligands.