Once infected, the only way to eliminate malaria-causing Plasmodium parasites from the body is via treatment with anti-malarial drugs. Alarmingly, Plasmodium falciparum (Pf) the parasite that causes most malarial deaths, is beginning to become resistant to front line artemisinin combination therapies in parts of Asia and there is concern this could spread globally. With new anti-malarial drugs urgently needed we attempted to develop compounds that could target protein kinase A (PKA), an essential parasite kinase important for replication of the disease-causing asexual blood stage. To target PfPKA we developed a novel series of compounds based on a 4-cyano-3-methylisoquinoline compound, a known inhibitor of rat PKA. Our lead compounds achieved modest parasite growth inhibition especially against the extracellular invasive merozoite parasite stages however further investigation revealed that the compounds did not target PfPKA. To find the genuine target we selected for resistance to our lead compound and sequenced the drug-resistant parasite genomes. Here we report that all resistant lines bore a single point mutation in the sodium efflux transporter PfATP4. To demonstrate our lead compound directly bound PfATP4 a biotinylated analogue was used to pull down the target protein from parasite lysates. PfATP4 is a leading drug target and several highly potent inhibitors have been developed that are under pre-clinical development.