Erythrocyte invasion byPlasmodium falciparumis central to the pathogenesis of malaria. Invasion requires a series of extracellular recognition events between erythrocyte receptors and ligands on the merozoite, the invasive form of the parasite. None of the few known receptor–ligand interactions involved1,2,3,4are required in all parasite strains, indicating that the parasite is able to access multiple redundant invasion pathways5. Here, we show that we have identified a receptor–ligand pair that is essential for erythrocyte invasion in all testedP. falciparumstrains. By systematically screening a library of erythrocyte proteins, we have found that the Ok blood group antigen, basigin, is a receptor for PfRh5, a parasite ligand that is essential for blood stage growth6. Erythrocyte invasion was potently inhibited by soluble basigin or by basigin knockdown, and invasion could be completely blocked using low concentrations of anti-basigin antibodies; importantly, these effects were observed across all laboratory-adapted and field strains tested. Furthermore, Oka− erythrocytes, which express a basigin variant that has a weaker binding affinity for PfRh5, had reduced invasion efficiencies. Our discovery of a cross-strain dependency on a single extracellular receptor–ligand pair for erythrocyte invasion byP. falciparumprovides a focus for new anti-malarial therapies.