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The erythrocyte membrane’s ability to withstand the stresses of circulation has its origins in various levels of structural organization. Central to this membrane’s structure-function relationships is a quasi-two-dimensional meshwork of spectrin-actin-protein 4.1 that imparts a resilence to the overlying plasma membrane. New insights into the nonlinear microelasticity of this substructure are being provided by experiments that range from elegant atomic force microscopy tests of single spectrin chains to patterned photobleaching of the micropipette-deformed network. Breakthroughs in atomic level structure determinations are further complemented by emerging biophysical studies of transgenically engineered mice lacking specific erythrocyte membrane proteins. Recent theoretical efforts (computational approaches most notably) also have begun to correlate molecular scale aspects of structure with mechanical measures. All of this recent activity in the biophysics of erythrocyte structure-function is certain to challenge and refine some of the most basic tenets in cell membrane structure-function.