Disorders of the erythrocyte membrane, such as hereditary spherocytosis, hereditary elliptocytosis, and hereditary pyropoikilocytosis, are characterized by heterogeneity in their clinical and laboratory manifestations. Recent work has shown that these disorders also exhibit marked genetic heterogeneity. Multiple genetic loci have been implicated, and various genetic defects, including gene deletions, point mutations, and defects in mRNA processing, have been described. The spherocytosis syndromes, with a few rare exceptions, are due to "private" mutations, ie, each individual kindred has a unique mutation. In contrast, the elliptocytosis/pyropoikilocytosis syndromes, although also quite heterogeneous, have been associated with distinct mutations in persons of similar genetic backgrounds, suggesting a "founder effect" for these mutations.