The only way to eliminate a malaria-causing Plasmodiumparasite infection is through treatment with anti-malarial drugs. Alarmingly Plasmodium falciparum(Pf) the parasite that causes most malarial deaths, is becoming 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 P. falciparumprotein kinase A (PfPKA), 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 known to inhibit rat PKA. Our lead compounds achieved modest parasite growth inhibition however further investigation revealed that the compounds did not target PfPKA. To find the biological target we selected for resistance to our lead compound MB14 and sequenced the drug-resistant parasite genomes. Here we report that all resistant lines bore a single point S374R mutation in the sodium efflux transporter PfATP4. Several inhibitors of PfATP4 are known and some are under preclinical development. Parasites resistant to PfATP4 inhibitors share properties with MB14 resistant mutant parasites such as slowed growth in culture. PfATP4 inhibitors also caused partial lysis of infected erythrocytes presumably due to the accumulation of Na+inside the parasites causing them to swell. We show that the Na+ions that enter parasites from the erythrocyte compartment first enter erythrocytes via new permeability pathways that are dependent on RhopH2 for their formation.