During leukocyte extravasation, integrin receptors can contribute to the rolling of leukocytes on the endothelium and they are essential for the firm adhesion of leukocytes to the vessel wall (Fig. 1). In addition, integrins play a role in the transmigration through the endothelium (1). All leukocytes express at least several of the 24 different integrins known so far, which are formed by heterodimerization of 18 α and 8 β subunits (2). Integrins can bind to endothelial receptors such as vascular cell adhesion molecule-1 and intercellular cell adhesion molecules to extracellular matrix molecules such as laminins and collagens, but also to other proteins such as the inactivated complement factor iC3b or bacterial polysaccharides. Because different integrins have different ligand-binding properties, the integrin expression pattern on the cell surface is determining where a leukocyte can leave the blood stream. In addition to their adhesive function, integrins are also important signaling receptors which after ligand binding initiate a variety of signaling cascades controling for example proliferation, apoptosis or lymphocyte activation (3). Chronic inflammation leads to changes in the expression and the activation of integrins on various leukocyte subsets, which promotes their extravasation into the inflammed tissues. Often, also the corresponding counter receptors are up-regulated on the endothelium of the inflammed tissues. Blocking the interaction of leukocyte integrins up-regulated during inflammation with their endothelial ligands could interfere specifically with unwanted extravasation while leaving all other extravasation processes intact. Leukocyte extravasation paradigm. Selectins and integrins mediate the initial contact between leukocytes and endothelium. Because the interactions are weak and not stable, the leukocytes roll on the endothelial wall driven by the blood flow. Chemokines secreted by the target tissue then lead to a quick increase of integrin affinity resulting in firm adhesion of the leukocytes to the endothelium. Finally, leukocytes cross the endothelial cell layer and underlying basement membrane and adhere and migrate in the extravascular tissue. Can this therapeutic approach help patients with chronic inflammatory diseases? Apparently yes. A recent study demonstrated a remarkable protective effect of α4 integrin-blocking antibodies in patients with relapsing multiple sclerosis (MS) (4). During a 6-month period of treatment with monthly injections of antibodies against α4 integrin, the number of new lesions was reduced by about 90%. Furthermore, the frequency of relapses decreased by 50%. Adverse effects during treatment were similar in patient groups treated with blocking antibody or placebo. Most likely, the antibodies prevent the extravasation of lesion inducing lymphocytes and monocytes into the brain. However, the therapeutic success might also be dependent on the blockade of α4 integrin signaling which could lead for example to impaired T-cell activation or the elimination of autoreactive T cells. Animal experiments support this view, because also antibodies against α4 integrin that do not impair leukocyte migration had a beneficial effect in autoimmune encephalitis (5). The therapeutic use of α4 antibodies is not restricted to MS. Also in Crohn's disease, a significant improvement has been reported in a clinical trial with antibodies against α4 integrin (5), and studies in animals showed efficacy in models for autoimmune arthritis, asthma, lupus erythematodes, vasculitis, and dermal inflammation and other inflammatory diseases (7–11). Not only α4 integrins could be a target for anti-inflammatory therapy. Recently, for example, it was shown that monoclonal antibodies against the collagen receptor α1β1 integrin protected mice from experimental colitis, prophylactic as well as therapeutic (12,13). Monocyte accumulation in the lamina propria was significantly reduced, although leukocyte binding to the endothelium seemed to be normal, pointing to a role of α1β1 in later steps of extravasation or in the retention of monocytes in the lamina propria. Clearly, monocyte activation was decreased by treatment with antibodies against α1β1 integrin. For widespread application, the high costs of the antibody treatment and the risk of an immune response are problematic. However, small molecular-weight inhibitors against α4β1 have been developed already and sucessfully tested in autoimmune encephalitis models in rodents (14–16). In addition, linear and cyclic peptides derived from integrin ligands have been shown to have inhibitory effects in vitro and in vivo (17). The best inhibitors are those that work in the clinic. In chronic inflammation, α4 integrin blockers seem to do exactly this. This work was supported by the German Research Council.