Significance: Plasmodium parasites have two distinct intracellular growth stages inside the mammalian host—the first stage, which is clinically silent, in liver hepatocytes, and the second, which causes the symptoms of malaria, in red blood cells. This study reports the discovery of a class of antimalarial compounds called torins, which are extremely potent inhibitors of both intracellular stages of Plasmodium . We show that torins block trafficking of liver stage parasite proteins to the physical host–parasite interface, called the parasitophorous vacuole membrane (PVM), and that without continuous trafficking of PVM-resident proteins, the parasite is subject to elimination by its host hepatocyte.