The human erythrocyte membrane has served as a model for elucidating novel protein-protein and protein-membrane interactions that have broad implications in many nonerythroid cells. A detailed analysis of erythrocyte membrane polypeptides that migrate in the region of band 4.9 led to the cloning and characterization of p55 phosphoprotein. Subsequent studies established that the p55 protein is an obligate component of the protein 4.1-glycophorin C complex, which regulates the stability and mechanical properties of the erythrocyte plasma membrane. p55 is a member of a growing family of signaling and cytoskeletal proteins termed membrane-associated guanylate kinase homologues (MAGUKs). MAGUKs are multidomain proteins consisting of either a single or three copies of the PDZ (PSD-95/Discs large/ZO-1) domain, an SH3 motif, and a guanylate kinaselike domain. Recent studies have implicated MAGUKs in the clustering of ion channels, organization of cytoskeletal elements, cell signaling events, and regulation of cell proliferation and tumor-suppression pathways. The purpose of this review is to summarize recent developments concerning the characterization of two human MAGUKs, erythrocyte p55, and lymphocyte hDIg.