We establish that in hamsters a dysregulated innate immune response is a driving force behind SARS-CoV-2 pathogenesis, in which in particular signal transducer and activator of transcription factor 2 (STAT2)-dependent type I and III IFN signaling plays a dual role: (i) restricting infection and dissemination on one hand but (ii) driving development of severe lung disease on the other. The gene discussed is STAT2; the disease is lung disorder.