Granulomas are chronic inflammations that prevent spread of poorly controllable infectious agents. The gut lumen contains enteric organisms that are excluded from the host by leukocytes located in the intestinal lining. Physiological intestinal inflammation and granulomas share some similarities. Both function to confine, but not necessarily abolish potentially harmful factors. Also, both are subject to intense immune regulation to avoid unnecessary tissue injury. Substance P and its natural analog hemokinin are produced at these sites of inflammation and are important components of this regulatory process. They act through a shared receptor (NK-1) expressed on T cells, macrophages, dendritic cells and probably other cell types. One of their functions is to enhance IFN-gamma production and amplify the Th1 response. The NK-1 receptor is an important target for immune regulation. Several Th1 cytokines and T cell antigen receptor (TCR) activation induce NK-1 receptor expression on T cells, while IL-10 and TGF-beta block receptor display. Macrophages also have an inducible NK-1 receptor. Various types of immune cells can make substance P and hemokinin, whose syntheses also are subject to immunoregulation. Thus, substance P and hemokinin are inflammatory cytokines with overlapping functions that help control immune responses in granulomas and at mucosal surfaces, and probably elsewhere.