Many pathogenic mycoplasmas are surface parasites, adhering to the epithelial linings of the respiratory and urogenital tracts. Since mycoplasmas lack cell walls their plasma membrane comes in close contact with that of their host, allowing exchange of components between the two membranes and possibly fusion. The tight association of the parasite with its host is illustrated in scanning electron micrographs of Mycoplasma pneumoniae and M. gallisepticum adhering to human red blood cells. Specialized structure at the tips of the mycoplasma cells appear to function as attachment organelles. Our main aim has been to chemically define the receptors on the host cell and the binding sites on the mycoplasma cells responsible for adhesion. Glycophorin (the major sialoglycoprotein of human red blood cells) serves as the main or sole receptor for M. gallisepticum whereas M. pneumoniae binds to additional receptors on human red blood cells. Trypsin treatment of M. pneumoniae cells abolishes their ability to attach to human red cells, suggesting the protein nature of the binding sites. M. pneumoniae membranes solubilized by detergents were subjected to affinity chromatography on glycophorin-Sepharose so that membrane components with high affinity for glycophorin could be isolated. The fraction isolated consisted of several proteins (relative molecular mass 25 000 and 45 000). The binding of this fraction to red cells was relatively low but appeared to be specific, as it was inhibited by glycophorin but not by its hydrophobic moiety. The possibility is discussed that the exposure of the binding sites on the mycoplasma cell surface is influenced by the electrochemical ion gradient across the membrane.