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The rapid emergence of resistance against new antimalarial drugs, including artemisinin\u2010based therapies, has made the development of drugs with novel mechanisms of action extremely urgent. Proteases are enzymes proven to be well suited for target\u2010based drug development due to our knowledge of their enzymatic mechanisms and active site structures. More importantly, <jats:italic>Plasmodium<\/jats:italic> proteases have been shown to be involved in a variety of pathways that are essential for parasite survival. However, pharmacological rather than target\u2010based approaches have dominated the field of antimalarial drug development, in part due to the challenge of robustly validating <jats:italic>Plasmodium<\/jats:italic> targets at the genetic level. Fortunately, over the last few years there has been significant progress in the development of efficient genetic methods to modify the parasite, including several conditional approaches. This progress is finally allowing us not only to validate essential genes genetically, but also to study their molecular functions. In this review, I present our current understanding of the biological role proteases play in the malaria parasite life cycle. I also discuss how the recent advances in <jats:italic>Plasmodium<\/jats:italic> genetics, the improvement of protease\u2010oriented chemical biology approaches, and the development of malaria\u2010focused pharmacological assays, can be combined to achieve a robust biological, chemical and therapeutic validation of <jats:italic>Plasmodium<\/jats:italic> proteases as viable drug targets.<\/jats:p>","DOI":"10.1111\/febs.14130","type":"journal-article","created":{"date-parts":[[2017,6,9]],"date-time":"2017-06-09T16:52:55Z","timestamp":1497027175000},"page":"2604-2628","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":76,"title":["Proteases as antimalarial targets: strategies for genetic, chemical, and therapeutic validation"],"prefix":"10.1111","volume":"284","author":[{"given":"Edgar","family":"Deu","sequence":"first","affiliation":[{"name":"Chemical Biology Approaches to Malaria Laboratory The Francis Crick Institute London 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