Malaria is one of the major diseases in the world. Due to the rapid spread of 
parasite resistance to available antimalarial drugs there is an urgent need for 
new antimalarials with novel mechanisms of action. Several promising targets for 
drug intervention have been revealed in recent years. This review addresses the 
parasitic aspartic proteases termed plasmepsins (Plms) that are involved in the 
hemoglobin catabolism that occurs during the erythrocytic stage of the malarial 
parasite life cycle. Four Plasmodium species are responsible for human malaria; 
P. vivax, P. ovale, P. malariae, and P. falciparum. This review focuses on 
inhibitors of the haemoglobin-degrading plasmepsins of the most lethal species, 
P. falciparum; Plm I, Plm II, Plm IV, and histo-aspartic protease (HAP). 
Previously, Plm II has attracted the most attention. With the identification and 
characterization of new plasmepsins and the results from recent plasmepsin 
knockout studies, it now seems clear that in order to achieve high-antiparasitic 
activities in P. falciparum-infected erythrocytes it is necessary to inhibit 
several of the haemoglobin-degrading plasmepsins. Herein we summarize the 
structure-activity relationships of the Plm I, II, IV, and HAP inhibitors. These 
inhibitors represent all classes which, to the best of our knowledge, have been 
disclosed in journal articles to date. The 3D structures of inhibitor/plasmepsin 
II complexes available in the protein data bank are briefly discussed and 
compared.