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As the indispensable oxygen-transporting cells, erythrocytes exhibit extreme deformability and amazing stability as they are subject to huge reversible shear stress and extrusion force during massive circulation in the body. The unique architecture of spectrin-actin-based membrane-skeleton is considered to be responsible for such excellent mechanical properties of erythrocytes. Although erythrocytes have been recognized for more than 300 years, myriad questions about membrane-skeleton constantly attract people’s attention. Here, we summarize the kinds of distinctive single-cell and single-molecule techniques that were used to investigate the structure and function of erythrocyte membrane-skeleton at macro and micro levels.