Sarco/endoplasmic reticulum Ca(2+)-ATPases (SERCAs) are increasingly being studied for therapeutic interventions in the fields of cancer, heart disease, and infection. Our suggestion a decade ago that artemisinins (the most important antimalarial class) act by inhibiting parasite SERCAs (PfATP6 and orthologues) expressed in Xenopus oocytes stimulated new directions for research away from conventional site-of-action studies of the food vacuole of the parasite. There is, however, still no consensus on how artemisinins act. We have continued to explore the hypothesis that PfATP6 is a key target by confirming that artemisinins inhibit Plasmodium falciparum PfATP6 when it is expressed in yeast and that it is essential for survival of pathogenic asexual-stage parasites. These advances are discussed with their implications for our understanding of how parasites regulate calcium in different stages of asexual development and for the global challenge posed by artemisinin resistance.