The human red blood cell membrane is a complex and well-studied system that provides insights into the molecular architecture of cell membranes. This review focuses on the localization and association of major polypeptides within the human red cell membrane. Red cell membranes can be purified through osmotic hemolysis and repeated washing, yielding "ghosts" that are essentially free of contamination. Proteins can be separated from lipids using polar organic solvents, revealing that approximately 52% of the membrane mass is protein, 40% is lipid, and 8% is carbohydrate. The amino acid composition of the erythrocyte membrane protein fraction is not distinctly different from other membranes, but individual proteins have characteristic compositions related to their membrane location. The protein fraction has a distinct excess of acidic residues, consistent with an apparent net isoelectric point of pH 4–5. The amino acid composition of the erythrocyte membrane protein fraction is not distinctly different from that of other membranes, but individual proteins have characteristic compositions related to their membrane location. The polypeptides in the red cell membrane can be separated by SDS-PAGE, revealing several major components, including glyceraldehyde 3-P dehydrogenase (G3PD), which has a molecular weight of approximately 35,000. These values are supported by independent evidence, such as gel filtration chromatography. The polypeptides are vulnerable to proteolytic degradation but not to dissociating agents. The polypeptide profiles from various mammalian erythrocyte sources closely resemble the human, with glycoprotein patterns being more diverse. Some ghost-associated proteins may be lost during erythrocyte maturation, at least in the rabbit. The red cell membrane exhibits an asymmetrical distribution of proteins, with some proteins confined to the outer surface and others to the cytoplasmic surface. This asymmetry is supported by various experimental approaches, including the use of probes and electron microscopy. The data suggest that the red cell membrane has an absolute asymmetry in the distribution of every protein constituent between the two surfaces. This is illustrated in Table II, which summarizes the sidedness of various erythrocyte membrane markers. The data support the hypothesis that the red cell membrane has an absolute asymmetry in the distribution of every protein constituent between the two surfaces. This asymmetry is further supported by the observation that certain proteins are not accessible in inside-out vesicles but are accessible in right-side-out vesicles. The data also suggest that some proteins span the membrane asymmetrically, with their carbohydrate portions detectable only at the outer surface. The data provide no support for proteins that are indifferent to vectorial topography or have more than one disposition. There is also no indication of polypeptide movement through the membrane thickness or rotation about an axis lying parallel to the plane of the membrane. The data suggest that the red cell membrane has an absolute asymmetry in the distribution of every protein constituent between theThe human red blood cell membrane is a complex and well-studied system that provides insights into the molecular architecture of cell membranes. This review focuses on the localization and association of major polypeptides within the human red cell membrane. Red cell membranes can be purified through osmotic hemolysis and repeated washing, yielding "ghosts" that are essentially free of contamination. Proteins can be separated from lipids using polar organic solvents, revealing that approximately 52% of the membrane mass is protein, 40% is lipid, and 8% is carbohydrate. The amino acid composition of the erythrocyte membrane protein fraction is not distinctly different from other membranes, but individual proteins have characteristic compositions related to their membrane location. The protein fraction has a distinct excess of acidic residues, consistent with an apparent net isoelectric point of pH 4–5. The amino acid composition of the erythrocyte membrane protein fraction is not distinctly different from that of other membranes, but individual proteins have characteristic compositions related to their membrane location. The polypeptides in the red cell membrane can be separated by SDS-PAGE, revealing several major components, including glyceraldehyde 3-P dehydrogenase (G3PD), which has a molecular weight of approximately 35,000. These values are supported by independent evidence, such as gel filtration chromatography. The polypeptides are vulnerable to proteolytic degradation but not to dissociating agents. The polypeptide profiles from various mammalian erythrocyte sources closely resemble the human, with glycoprotein patterns being more diverse. Some ghost-associated proteins may be lost during erythrocyte maturation, at least in the rabbit. The red cell membrane exhibits an asymmetrical distribution of proteins, with some proteins confined to the outer surface and others to the cytoplasmic surface. This asymmetry is supported by various experimental approaches, including the use of probes and electron microscopy. The data suggest that the red cell membrane has an absolute asymmetry in the distribution of every protein constituent between the two surfaces. This is illustrated in Table II, which summarizes the sidedness of various erythrocyte membrane markers. The data support the hypothesis that the red cell membrane has an absolute asymmetry in the distribution of every protein constituent between the two surfaces. This asymmetry is further supported by the observation that certain proteins are not accessible in inside-out vesicles but are accessible in right-side-out vesicles. The data also suggest that some proteins span the membrane asymmetrically, with their carbohydrate portions detectable only at the outer surface. The data provide no support for proteins that are indifferent to vectorial topography or have more than one disposition. There is also no indication of polypeptide movement through the membrane thickness or rotation about an axis lying parallel to the plane of the membrane. The data suggest that the red cell membrane has an absolute asymmetry in the distribution of every protein constituent between the