Interactions between neural and immune effector pathways serve a vital role in mammalian defenses against foreign pathogens and toxins. The immune system initiates processes leading to the release of diverse mediators and cytokines that recruit neural and endocrine involvement in immunity. Inversely, transmitters released from nerves innervating immune organs regulate the development and functions of the immune cells. Vasoactive intestinal peptide (VIP) is the quantitatively and functionally most prominent immunoregulatory neuropeptide that participates in local tissue immune responses by potently affecting T cell and macrophage migration, proliferation, and cytokine production. T cells, macrophages, and mast cells express the VIP G protein–coupled receptors (GPCR) VPAC1 and VPAC2 that transduce the effects of VIP on immunity. The VIP–VPAC axes also are coupled to abnormal T cell functions in different autoimmune conditions. Recently, it has been shown that VIP also enhances the differentiation of distinctive type of proinflammatory Th17 cells by a VPAC1-dependent mechanism. This unique VIP–VPAC1 signaling in Th17 cell differentiation expands our understanding of VIP immune functions, provides new insights into the immune roles of individual VPAC receptors, and offers meaningful possibilities for improving therapeutic potential of VIP in immune disorders.