CD44 is a widely distributed type I transmembrane glycoprotein and functions as the major hyaluronan receptor on most cell types. Although alternative splicing can produce a large number of different isoforms, they all retain the hyaluronan-binding Link-homology region and a common transmembrane and cytoplasmic domain, which are highly conserved between species. The past decade has seen an extensive investigation of this receptor owing to its importance in mediating cell-cell and cell-matrix interactions in both normal and disease states. Although roles for alternative splicing and variable glycosylation in determining ligand-binding interactions are now well established, the mechanisms by which CD44 integrates structural and signalling events to elicit cellular responses have been less well understood. However, there is now increasing evidence that CD44 is assembled in a regulated manner into membrane-cytoskeletal junctional complexes and, through both direct and indirect interactions, serves to focus downstream signal transduction events.