Multidrug-resistant forms of Plasmodium falciparum contribute directly to the massive global burden of malaria, which, as of 2015, impacts nearly 200 million people and result in over 400,000 deaths per year. P. falciparum resistance to the former first-line drugs chloroquine and pyrimethamine-sulfadoxine has now exacerbated the emergence and spread of resistance to the current first-line drug artemisinin (ART) and some partner drugs used in first line artemisinin (ART)-based combination therapies (ACTs). To achieve the stated goal of malaria elimination, new therapeutic strategies are essential to eliminate multi-drug resistant parasites. Recent studies of ART-resistant parasite strains suggest that they can resist drug-mediated killing by up-regulation of the unfolded protein response (UPR), a process that depends on activation of the multi-catalytic proteasome complex. Consequently, proteasome inhibitors have been shown to be highly synergistic with ART derivatives. Unlike ART, these inhibitors are also active liver, gametocyte and oocyst stages. Therefore, compounds that selectively target the Plasmodium proteasome have the potential to be curative while also blocking transmission from human to insect vector and reducing the emergence of drug resistance. We hypothesize that ART, as well as other classes of current anti-malarial drugs and preclinical candidates, induce stress pathways in P. falciparum that depend on proteasomal activity to achieve resistance. We also hypothesize that proteasome inhibitors have the potential to be broadly used to suppress the onset of multidrug resistance in native parasite populations. This proposal is built around strong preliminary results using substrate screening assays and our recently solved cryo-electron microscopy structure of the P. falciparum 20S proteasome to design selective inhibitors of the parasite proteasome with nanomolar potency that effectively clear rodent malaria infections in vivo. We find that proteasome inhibitors show a high degree of synergism when combined with ART and are potent against ART-resistant field isolates. Our preliminary results therefore establish the paradigm that the proteasome is a viable anti-malarial drug target. We propose developing improved parasite-specific proteasome inhibitors that have enhanced potency, selectivity and bioavailability while simultaneously defining the mechanism and conditions by which inhibitors can optimally synergize with anti-malarial agents to prevent the spread of resistance.