Viral pandemics,such as the one caused by SARS-CoV-2,pose an imminent threat to humanity. Because of its recent emergence, there is a paucity of information regarding viral behavior and host response following SARS-CoV-2 infection. Here, we offer an in-depth analysis of the transcriptionalresponse to SARS-CoV-2 as it compares to other respiratory viruses.Cell and animal models of SARS-CoV-2 infections, in addition totranscriptional and serum profiling of COVID-19 patients,consistently revealedaunique and inappropriate inflammatory response. This response isdefined bylow levels of Type I and III interferons juxtaposed toelevated chemokinesand high expression of IL-6. Taken together, we propose that reduced innate antiviral defenses coupled withexuberant inflammatory cytokineproduction arethedefining and driving feature ofCOVID-19.