To address this, we have focused on targeting malaria parasite protein kinases that we identified as essential for blood stage parasite survival. Emerging from these studies has been a focus on the P. falciparum cyclin-dependent like protein kinase-3 (PfCLK3), one of a family of 4 protein kinases with a role in the phosphorylation and assembly of components of the spliceosome. A screen of the GlaxoSmithKline anti-malarial focused chemical library, called the Tres Cantos Anti-Malarial Set (TCAMS), identified the compound TCMDC-135051 1 (Fig. ) as a selective PfCLK3 inhibitor. This tool inhibitor was used in combination with genetically engineered parasite lines and field isolates to validate PfCLK3 as a target with the potential to deliver a cure for blood stage infection, as well as preventing the development of gametocytes responsible for transmission and parasiticidal activity of liver stage in a manner that can be prophylactic. TCMDC-135051 (1) has since entered a drug development programme aimed at generating a clinical candidate that is curative, transmission blocking and offering prophylaxis across Plasmodium sp. One of the major challenges faced in developing next generation anti-malarials is the requirement to produce a single dose medicine that is highly tolerated and safe to be administered to young children and pregnant women. That the erythrocytic stage of the parasite has a 48 hour cycle (Fig. ); that the parasite can sequester in tissue such as bone marrow; that the gametocyte stages can take many days to develop; and that stage V gametocytes remain in the circulation for several weeks, means that any effective anti-malarials need to act at multiple stages of the parasite life cycle for long periods. Whereas inhibitors of PfCLK3 are effective at multiple parasite stages, correlating with the importance of RNA-splicing in the biology of the parasite, the question of long exposure at the target is an important issue. A potential strategy to deliver extended exposure is to build in favourable pharmaco-dynamic properties through the application of covalent inhibitors, which irreversibly bind to the target. This approach has been employed in targeting protein kinases in oncology, where covalent inhibitors have shown increased potency, selectivity and decreased propensity to resistance. Despite the unquestionable success of targeting protein kinases in cancer, the exploitation of protein kinase inhibitors in malaria is in its infancy. What has certainly never been explored is the potential of covalent kinase inhibitors as effective anti-malarials. Here we employ a high-resolution atomic structure of TCMDC-135051 (1) in complex with PfCLK3 to inform structure-guided design of a covalent inhibitor that targets a non-conserved cysteine residue proximal to the catalytic site of PfCLK3. Protein mass spectrometry and live parasite wash-out experiments confirmed successful covalent modification of the target cysteine.