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The tetraspanins are a family of plasma membrane proteins that contain four transmembrane domains and a trademark Cys-Cys-Gly motif in a large extracellular loop between transmembrane domains 3 and 4. They are implicated in various processes, including cell migration, proliferation and differentiation, but no physiological receptor/ligand has been identified, and there are few clues to their cell biological role(s). Fedor Berditchevski reviews accumulating evidence that one role of tetraspanins is to regulate integrin function. Several integrins have been shown to associate with tetraspanins as part of a ‘tetraspanin web’, and recent work indicates that tetraspanins can modulate integrin-dependent cell migration. Given that tetraspanins associate with signalling molecules such as phosphatidylinositol 4-kinase and protein kinase C, they might also facilitate adhesion-dependent integrin signalling by tethering such enzymes to integrins. This compartmentalization could extend to formation of tetraspanin-rich membrane microdomains, since integrins and tetraspanins co-localize with the lipid raft component GM1. Furthermore,...