Plasmodium parasites, the causative agents of malaria, have developed resistance to most of our current antimalarial therapies, including artemisinin combination therapies which are widely described as our last line of defense. Antimalarial agents with a novel mode of action are urgently required. Two Plasmodium falciparum aminopeptidases, PfA-M1 and PfA-M17, play crucial roles in the erythrocytic stage of infection, and have been validated as potential antimalarial targets. Agents that inhibit the aminopeptidase enzymatic activity in parasites have been shown to control both laboratory and murine models of malaria. Similarly, the enzymes are highly conserved amongst all Plasmodium species, indicating that future therapuetics could deliver cross-species inhibition. Using compound-bound crystal structures of both enzymes, we have used a structure-guided approach to develop a novel series of inhibitors capable of potent inhibition of both PfA-M1 and PfA-M17 activity, and parasite growth in culture. Here we present our latest results on the structural and functional studies on the P. falciparum aminopeptidases.