Hereditary spherocytosis is a common and very heterogeneous hemolytic anemia caused by defects of the red cell membrane proteins. In recent years, major advances in our understanding of the red cell membrane skeleton and a better characterization of its individual components have allowed a brighter insight into the pathogenesis of the disease. In this article, we present an overview of the erythrocyte skeleton and its individual constituents. We also review the clinical aspects of the disease and describe the currently known molecular defects involving the membrane proteins which have been shown to play an essential role in the underlying mechanism of hereditary spherocytosis. Finally we examine several models that have been proposed in an attempt to clarify the mechanism leading from the initial molecular insult to the clinical phenotype.