Carukia barnesi (colloquially referred to as ‘Irukandji’) is a species of highly venomous jellyfish found in northern Australian waters with an extraordinarily painful and potentially lethal sting. Envenomation causes ‘Irukandji Syndrome’, involving intense pain, a sense of impending doom, and cardiovascular dysfunction leading to death. C. barnesi venom and its mechanism of action on cells remains largely uncharacterised. We have used a FACS-based CRISPR screening strategy to investigate changes in Ca2+ responses after venom exposure. From this we identified a candidate C. barnesi venom receptor and validation of hits is underway. Our research has the potential to inform treatment strategies for C. barnesi envenomation, and guide development of new therapies targeting pain, cardiovascular disease or sense of doom.