For decades, research has demonstrated that chronic diseases characterized by dysregulation of inflammation are particularly susceptible to exacerbation by stress and emotion. Likewise, rates of depression and anxiety are overrepresented in individuals suffering from chronic inflammatory disease. In recent years, substance P has been implicated in both the pathophysiology of inflammatory disease and the pathophysiology of depression and anxiety by 2 parallel fields of study. This review integrates the literature from these 2 parallel fields and examines the possibility that substance P dysregulation may be a point of convergence underlying the overlap of chronic inflammatory disease and mood and anxiety disorders. First, the involvement of substance P in peripheral inflammation and in the immune events associated with chronic inflammatory disease is discussed, with a focus on inflammatory bowel disease and asthma. Next, the function of substance P in the communication of peripheral inflammation to the brain is considered. Finally, to complete the bidirectional loop of brain-immune interactions, substance P expression in anxiety and depression as well as its potential role in the neural regulation of peripheral inflammation is reviewed.