Plasma membranes of metazoan cells are the site of convergence of disparate sets of molecules located in intercellular, transmembrane, and cytoplasmic compartments. Coordination between these compartments results in special ized cell domains and is essential for initial organization of cells into tissues during development, as well as physiological functions of cells in adult tissues. What is the structural basis for organization on the scale of cell domains? Conventional electron microscopy reveals an electron-dense un dercoat as a common feature of many cell membranes, and such undercoats are especially well developed in specialized regions of the plasma membrane. Analysis of these multiprotein c; omplexes at a molecular level is especially challenging due to the large number of components and their size, which can extend to microns. Moreover, these structures, although organized, are not sufficiently ordered for analysis by X-ray or electron diffraction. Striking images of the polygonal spectrin-actin network of erythrocytes (Byers & Branton 1985; Liu et al 1987) suggest that, at least in some cases, the apparently amorphous material associated with membranes actually represents organized assemblies of proteins. Spectrin-based structures, per haps closely related to the erythrocyte membrane skeleton, are a feature of many cells, since spectrin and associated proteins are ubiquitous components of metazoan plasma membranes. Functions of spectrin are likely to be diverse in different cells, but related in general to coupling of a variety of membrane-spanning cell surface proteins to cytoplasmic elements. This review deals with the current understanding of the spectrin skeleton in terms of its constituent proteins and the potential physiological and clinical relevance of these proteins in cells more complex than erythrocytes. Insights from this body of work may be useful in designing strategies for resolving other cell structures.