Abstract: The major immunoregulatory effects of vasoactive intestinal peptide (VIP) are mediated by structurally distinct type I (VIPR1) and II (VIPR2) G protein-associated receptors on many different types of immune cells. VIP is released in functionally relevant concentrations during many immunologic and inflammatory responses. Mast cells (VIPR1), macrophages (VIPR1 and VIPR2), B cells, and T cells (VIPR1, VIPR2, or VIPR1 and VIPR2) recognize and respond to VIP in patterns that are controlled by the relative levels of expression of VIPR1 and VIPR2. VIPR2 transduces human T-cell chemotaxis, expression of matrix metalloproteinases (MMPs) 2 and 9 and consequently basement membrane and connective tissue transmigration, while signaling suppression of proliferation and cytokine production. In contrast, VIPR1 fails to transduce T-cell chemotaxis but mediates suppression of chemotaxis and MMP expression elicited by some cytokines and chemokines. The relative representation of each type of VIPR, which is presumed to be under cytokine control, thus may determine T-cell responses to VIP and other immune mediators in tissue compartments innervated by VIPergic nerves.