Malaria is caused by intracellular parasites of the genus Plasmodium. Protein translation occurs in three compartments within Plasmodium parasites: the cytosol, the mitochondrion and a relic plastid called the apicoplast. Aminoacyl tRNA synthetases must charge tRNA for each of these compartments but Plasmodium encodes too few tRNA synthetases to allow a unique enzyme for each amino acid in all compartments. The tRNA synthetases for Ala, Cys, Gly, and Thr are found only once in the genome and we show that each of these enzymes is dual targeted to the Plasmodium falciparum cytosol and the apicoplast. No mitochondrial localisation is apparent for any Plasmodium tRNA synthetase. For three of these enzymes dual trafficking appears to be mediated by alternate translation initiation, but for CysRS, dual localisation is facilitated by alternate splicing that produces isoforms with and without apicoplast targeting sequences. Because of the dependence of Plasmodium parasites on efficient translation, this process is a promising drug target. We have taken two approaches to drug discovery against Plasmodium tRNA synthetases – one is to inhibit the bacterial-like aaRSs that service the apicoplast based on existing anti-bacterial inhibitors, the other is to pursue novel and existing inhibitors of the dual targeted aaRSs that serve functions in both the cytosol and the apicoplast. We show that inhibitors of bacterial-type aaRSs lead to delayed death phenotypes and defects in apicoplast morphology and segregation, while inhibitors of the dual targeted aaRSs lead to immediate death and inhibit nascent protein synthesis as well as activity of recombinant tRNA synthetase. We have isolated stable parasite lines that are resistant to several of these aaRS inhibitors and are investigating the mode of resistance in these mutants. Inhibitors of dual targeted tRNA synthetases, in particular, should have a rapid mode of action that blocks parasite proliferation, as well as mopping up surviving parasites by leading to loss of apicoplast.