Baro et al demonstrate that the red cell surface receptor CD44 plays an important role in P falciparum invasion by interacting with EBL family proteins EBA-175 and EBA-140 as a coreceptor, mediating parasite-induced signaling to the host cell cytoskeleton important for red cell invasion. Subsequent steps involve discharge of the rhoptry contents, formation of the moving junction, and internalization, which require additional ligand-receptor interactions, together ensuring formation of the parasitophorous vacuole and efficient invasion. AMA1, apical membrane antigen 1; CR1, complement receptor 1; CyrPA, cysteine-rich protective antigen; PCRCR, pentameric complex; PfEBA, Plasmodium falciparum EBA; PfRh, reticulocyte-binding protein homolog; RON, phoptry neck protein.