Underlying the human erythrocyte membrane is a self-assembled network of proteins termed the membrane skeleton. This network plays a major role in conferring a biconcave shape on the normal erythrocyte and maintaining mechanical properties of the human erythrocyte membrane. Spectrin, actin, protein 4.1, adducin, tropomyosin, dematin and p55 are the principal components of the membrane skeleton. Lateral interactions among these proteins constitute the spectrin-based composite structure that is anchored to the bilayer through vertical interactions, one involving beta-spectrin, ankyrin and band 3, and the other through an interaction between protein 4.1 and glycophorin C. In this article reviewed are biochemical structure of the skeletal proteins, their interactions and regulations by various constituents based on recent studies.