Malaria is one of the major parasitic disease whose rapid spreading and 
mortality rate affects all parts of the world especially several parts of Asia 
as well as Africa. The emergence of multi-drug resistant strains hamper the 
progress of current antimalarial therapy and displayed an urgent need for new 
antimalarials by targeting novel drug targets. Until now, several promising 
targets were explored in order to develop a promising Achilles hill to counter 
malaria. Plasmepsin, an aspartic protease, which is involved in the hemoglobin 
breakdown into smaller peptides emerged as a crucial target to develop new 
chemical entities to counter malaria. Due to early crystallographic evidence, 
plasmepsin II (Plm II) emerged as well explored target to develop novel 
antimalarials as well as a starting point to develop inhibitors targeting some 
other subtypes of plasmepsins i.e. Plm I, II, IV and V. With the advancements in 
drug discovery, several computational and synthetic approaches were employed in 
order to develop novel inhibitors targeting Plm II. Strategies such as fragment 
based drug design, molecular dynamics simulation, double drug approach etc. were 
employed in order to develop new chemical entities targeting Plm II. But 
majority of Plm II inhibitors suffered from poor selectivity over cathepsin D as 
well as other subtypes of plasmepsins. This review highlights an updated account 
of drug discovery efforts targeting plasmepsin II from a medicinal chemistry 
perspective.