Depression and anxiety are among the most common diseases in the United States, thus constituting a substantial financial burden for the health care system. Experimental studies of these affective disorders to date have largely focused on the neurotransmitter pathways with well-established pathophysiologic roles, such as serotonergic, noradrenergic, and gamma-aminobutyric acid (GABA)-ergic systems; agents modulating the activity of these pathways are known to be clinically effective. More recently, the neuropeptide substance P (SP) and its receptor (the neurokinin-1 receptor [NK1R]) have been implicated in the pathophysiology of affective disorders, including depression. Earlier preclinical and clinical studies, though, did not provide a clear consensus on the role of SP in the regulation of affective behavior and related pathologic conditions. Recent studies in mice clearly demonstrate that both the genetic disruption and acute pharmacologic blockade of the NK1R result in marked reduction in anxiety-like behavior and stress-related responses. In parallel with these behavioral effects, physiologic changes, such as an increased firing rate of 5-hydroxytryptamine (5-HT) neurons in the dorsal raphe nuclei and a desensitization of presynaptic 5-HT1A inhibitory autoreceptors, were observed. These findings provide further evidence for the regulatory role of the SP-NK1R system in modulation of affective behavior and indicate that its effects are mediated, at least in part, via the serotonergic system. Future studies will attempt to delineate the interaction between the SP-NK1R system and various neurotransmitter pathways in greater detail and to address the specific role(s) of this system in different brain regions.