Liver infection by Plasmodium spp. sporozoites is a crucial initial step in the life cycle of malaria parasites; however, the underlying molecular mechanisms are still poorly understood. Now, a new study provides molecular insights into hepatocyte invasion by Plasmodium spp. sporozoites. The authors showed that the human parasites Plasmodium falciparum and Plasmodium vivax use two distinct host cell receptors, CD81 and scavenger receptor class B type I (SR-BI), respectively, to enter hepatocytes. By contrast, the same receptors were functionally redundant for the entry of the rodent parasite Plasmodium berghei. In addition, they found that the parasite protein P36, which is a member of the 6-cysteine domain protein family, is a key determinant of receptor use. This study sheds light on the pathways that are used by malaria parasites to enter liver cells and reports new functional receptor–ligand interactions on hepatocytes.