The box jellyfish Chironex fleckeri is the most venomous animal on the planet, with significant skin contact leading to extreme pain and death within minutes. Currently the only accepted emergency response to envenomation is continuous CPR to prevent death. Despite its potent actions on the nociception and cardiovascular systems, there is a lack of basic molecular insight into how this venom works. Here we perform the first ever molecular dissection of the jellyfish venom death pathway. We used genome-scale lenti-CRISPR mutagenesis with ~123,000 guide RNAs targeting all coding human genes and some noncoding RNA, screening for host components required for death after venom exposure. We identified hundreds of human genes that, when targeted, confer some resistance to box jellyfish venom. Among the host factors most enriched in our screen was the peripheral membrane protein ATP2B1, a calcium transporting ATPase implicated in the regulation of blood pressure and a likely candidate for the venom receptor. Jellyfish venom resistance in the absence of ATP2B1 was confirmed in multiple cell types and this protection was long lasting. Analysis of venom resistance genes highlighted numerous new pathways not previously implicated in cell death, and we have further validated many of these factors are required for box jellyfish-mediated death. Guided by these data, we have tested multiple compounds that target the box jellyfish death pathway, and have identified a new “anti-venom” drug that can completely suppress cell death even when added up to 15 minutes after venom exposure. This compound is safe for human use, stable at room temperature, and may represent a new therapy for box jellyfish and potentially other venoms. These results highlight the power of whole genome CRISPR screening to investigate unknown molecular mechanisms and new biology.