The alpha4 integrins (alpha4beta1 and alpha4beta7) play multiple roles in the immune system. Alpha4 integrins impact hematopoiesis, leukocyte trafficking in immune surveillance and inflammation, and leukocyte activation and survival. To perform these functions, alpha4 integrins act as both adhesive and signaling receptors. Paxillin, a signaling adapter molecule, binds directly to the alpha4 subunit cytoplasmic domain, and its binding is regulated by serine phosphorylation of the alpha4 subunit. This regulated interaction of paxillin with the alpha4 subunit is likely to regulate the diverse functions of alpha4 integrins in the immune system. Furthermore, this protein-protein interaction may provide novel targets for the modulation of the immune response.