Plasmepsins (Plms) are aspartic proteases involved in the degradation of human 
hemoglobin by Plasmodium falciparum. Given that the parasite needs the resulting 
amino acid building blocks for its growth and development, plasmepsins are an 
important antimalarial drug target. Over the past decade, tremendous progress 
has been achieved in the development of inhibitors of plasmepsin using two 
strategies: structure-based drug design (SBDD) and structure-based virtual 
screening (SBVS). Herein, we review the inhibitors of Plms I-IV developed by 
SBDD or SBVS with a particular focus on obtaining selectivity versus the human 
Asp proteases cathepsins and renin and activity in cell-based assays. By use of 
SBDD, the flap pocket of Plm II has been discovered and constitutes a convenient 
handle to obtain selectivity. In SBVS, activity against Plms I-IV and 
selectivity versus cathepsins are not always taken into account. A combination 
of SBVS, SBDD, and molecular dynamics simulations opens up opportunities for 
future design cycles.