Parasite aspartic peptidases (pAP) have been considered as potential therapeutic targets for a long time. Known roles of pAPs include protein trafficking in apicomplexan parasites best demonstrated by plasmepsin V and its Toxoplasma gondii homologue TgASP5. Our results with Cre-dependent excision of TgASP5 revealed parasitophorous vacuole damage, severe loss in parasite fitness in vitro and an altered virulence in vivo suggesting an impaired modulation of host immune responses. pAPs also play primary roles in blood digestion in malaria, platyhelminths, nematodes and some arthropod vectors. In addition to the previously characterized tick IrCD1 – a structurally unique aspartic hemoglobinase contributing to the cysteine peptidase complex in the guts of Ixodes ricinus, we discuss here the role of newly characterized IrCD2 as a “late” and possibly secreted tick gut aspartic peptidase. Obviously, the phylogeny of pAPs is triggered by the need for various biological functions as a part of adaptation to parasitic lifestyle. Besides identification of pAPs from newly sequenced genomes and EST datasets, structural and expressional differences among multiple pAP isoenzymes within one parasite should be carefully described prior their validation as therapeutic targets. Also, focusing on a single enzyme target in a metabolic event such as hemoglobin digestion has been shown to be a flawed concept - blood digestive plasmepsins were long thought to be therapeutic targets and were disappointingly not proven to be essential malarial enzymes by multiple gene knock-outs. We show in the current presentation that the rapidly evolving functional-genetic tools in combination with biochemical and structural characterization ultimately lead to rational hypotheses and experiments elucidating particular roles and functions of pAPs working in complexes. Knowledge on function and regulation of pAP has dramatically progressed during the last decade and we specifically highlight novel trends and possible implications for the development of novel anti-parasitic compounds.