The obligate intracellular pathogens Plasmodium falciparum and Toxoplasma gondii remodel their host cell to facilitate their intracellular development and progress through their asexual life cycle, a virulent lytic cycle responsible for parasite-mediated pathogenesis. While several studies have highlighted parasite proteins that interact with the host cell during this cycle, host proteins exploited by the parasite for successful growth and conversely, host molecules evolutionarily tuned to control parasite infection remain unclear. We addressed this question from both sides of the host-parasite interaction in the hope to leverage biological discovery of host molecules involved in infection into the validation of novel drug target candidates with vastly reduced potential for resistance: (1) building on previously established roles of host calpain during the lytic cycle to elucidate host pathways that facilitate parasite life cycle progression and (2) clarifying the existing role of platelets in innate control of parasitic disease. Comparative proteomics, genetics, and biochemical techniques led us to the discovery of a complex Gaq-coupled, protein kinase C (PKC)-mediated host signaling cascade common to both T. gondii and P. falciparum that results in cytoskeletal compromise and facilitates host calpain activation immediately prior to parasite release (Millholland et al., 2011; Millholland et al., 2013). The complexity of this pathway represented an untapped resource of antimalarial targets; indeed, inhibitors of key host signaling components demonstrated antiparasitic activity in murine models of malaria and toxoplasmosis. Conversely, host platelets were previously shown to have antimalarial capacity, leading us to characterize this host-parasite interaction in the hope to harness this antimalarial activity to optimize therapeutic potential. Upon screening molecules secreted in the blood stream, we identified Platelet Factor 4 as the host defense peptide (HDP) component of platelets capable of killing malaria parasites via selective lysis of the parasite digestive vacuole (DV), the site of hemoglobin digestion(Love et al., 2012). To exploit this DV lysis mechanism in a drug discovery effort, we tested a library of small, nonpeptidic mimics of HDPs and identified compounds that potently killed P. falciparum in vitro and reduced parasitemia in a murine malaria model. Taken together, these data reinforce the feasibility of targeting host molecules as a novel antiparasitic strategy.