Malaria is a life-threatening infectious disease caused by Plasmodium parasites. Plasmepsins (proteolytic enzymes of the parasite) have been considered as promising targets for the development of antimalarial drugs. To date, much knowledge has been obtained regarding the interactions of inhibitors with plasmepsins, as well as the structure–activity relationships of the inhibitors. The discovery and characterization of the plasmepsin inhibitors that bind in open flap conformation have led to several inhibitor classes that show high selectivity over other human aspartic proteases. This Perspective addresses the flexibility of the plasmepsins that leads to inhibitor binding to the open flap conformation, summarizes known nonpeptidomimetic plasmepsin inhibitors, and discusses the role of the inhibitor flap pocket substituent.