We are studying the structure and function of malarial proteins inserted into and though the membrane of erythrocytes infected with mature asexual malaria parasites and molecules on the endothelial cells involved in cytoadherence. Two very large (Mv about 300,000) P. falciparum proteins have been localized to the surface membrane of infected erythrocytes. One protein is exposed on the cell surface and appears to mediate attachment to endothelial cells. The other malarial protein is localized under the membrane at the knob protrusions which mediate cytoadherence. These proteins do not appear to be related structurally. A third P. falciparum protein of unusually high histidine content has also been localized to the submembrane material under knobs. The histidine-rich protein is a structural or functional component of knobs but does not directly confer cytoadherence. Immunoelectonmicroscopy studies of P. falciparum isolates from West African patients have shown that the isolate-specific and pan-specific cell surface epitopes defined by homologous and heterologous African sera are both localized on the knob protrusions. The potential role of thrombospondin as the host cell ligand for cytoadherence has been studied in more detail. The stage-specificity of attachment of infected cells to thrombospondin and trypsin-sensitivity of the infected cell surface component involved in attachment to this protein match the properties of attachment to endothelial cells. We have also shown that the domain of thrombospondin involved in heparin binding is not involved in attachment of infected erythrocytes. We have also sequenced two P. falciparum genes encoding proteins of extraordinary histidine content, one of which is exported through the host erythocyte surface membrane into the plasma.