Liver invasion is an essential step for the establishment of malaria. Sporozoites, which are the transmitted parasite stages, invade hepatocytes to establish productive infection in the parasitophorous vacuole. Kaushansky et al. now shed light on the molecular mechanism underlying this process. They show that ephrin receptor A2(EPHA2) determines hepatocyte permissiveness to infection; hepatocytes with high EPHA2 expresssion were preferentially infected. Furthermore, Epha2−/− mice showed reduced infection with Plasmodium yoelii, as did wild-type mice infected with parasites lacking the P52 and P36 surface proteins, which contain ephrin domains.