Migratory cells use both adhesion receptors and proteolytic enzymes to regulate their interaction with and response to extracellular matrices. Cooperation between integrins and proteases operates at several levels: integrin signaling induces proteases, proteases co-localize with integrins, and proteases regulate the interface between integrins and the intracellular cytoskeleton. One protease system intimately connected to integrins is the urokinase/urokinase receptor(uPAR)/plasmin system. Recent studies indicate urokinase promotes the ligand-like binding of its receptor to a set of beta1 and beta2 integrins, this binding in turn affecting integrin signaling and cell migration. The glycolipid anchor of uPAR associates with cholesterol-rich membrane rafts. Binding of uPAR to integrins may enrich integrin clusters with signaling molecules such as src-family kinases that localize to rafts and are important to integrin function. Signals derived from integrin/uPAR complexes promote the function of other integrins. Thus the urokinase/plasmin system coordinates with integrins to regulate cell: matrix interactions.