The recruitment of leukocytes into tissue is a pivotal step in inflammation. alpha4-Integrins are adhesion receptors on circulating leukocytes that mediate attachment to the endothelium and facilitate their migration into the inflamed tissue. This multistep process is mediated by the interaction of alpha4-integrins with their counter receptors VCAM-1 and MadCAM-1 that are expressed on endothelial cells. alpha4-Integrins act as both adhesive and signaling receptors. Paxillin, a signaling adaptor molecule, binds directly to the alpha4 cytoplasmic tail and its binding is important for cell migration. Blocking the adhesive functions of alpha4-integrins has been shown to be an effective therapeutic approach in the treatment of autoimmune diseases, but also carries the risk of defects in development, hematopoiesis and immune surveillance. Interfering with alpha4 signaling by inhibiting the alpha4-paxillin interaction decreases alpha4-mediated cell migration and adhesion to VCAM-1 and MadCAM under shear flow. These in vitro effects are accompanied by a selective impairment of leukocyte migration into inflammatory sites when the alpha4-paxillin interaction is blocked in vivo. Thus, blockade of alpha4-integrin signaling may offer a novel strategy for interfering with the functions of these receptors in pathological events while sparing important physiological functions.