The known role of NLRP3 in hyperinflammatory ARDS and CRS, documented NLRP3 involvement in MERS-CoV and SARS-CoV severity, and apparent efficacy of anti-NLRP3 therapeutics in SARS-CoV and SARS-CoV-2 clinical trials and animal models strongly indicate that NLRP3 is a central mediator of severe COVID-19. The gene discussed is NLRP3; the disease is COVID-19.