SARS-CoV-2 emerged in late 2019, with much evidence tracing the initial human spillover to a market with extensive human-animal contact. As the coronavirus spread in its new host species, multiple variants of concern representing distinct genetic lineages appeared and propagated globally. Ongoing viral evolution has increased transmission, and also evasion of neutralizing antibodies (adaptive arm of the immune system). Hence, many important studies have deservedly focused on dissecting consequences of Spike protein mutations in different emerged variants. However, mutations have also been detected in viral genes other than Spike, and several of these genes are linked to antagonism of innate immune responses. We provide detailed evidence that compared to ancestral or early SARS-CoV-2 isolates, the five major variants of concern so far (alpha, beta, gamma, delta and omicron) have become more resistant to multiple human interferons that included the 12 IFNα subtypes, IFNβ, IFNω and 3 IFNλ subtypes1. The underlying mechanisms for these IFN resistance phenotypes are unclear and, paralleling the four decades it has taken to understand innate immune evasions mediated by the proteins encoded by the nine genes of HIV-1, a full picture for SARS-CoV-2 will require sustained investigation over time. However, in both the short and long terms, the scientific and medical impacts of characterizing resistance of this newly emerged coronavirus mechanistically can be highly significant, for not only the current pandemic but potentially also for future sarbecovirus spillover events. We thus propose to build on our ample published1 and unpublished preliminary data and accumulated experience to track the evolution of SARS-CoV-2 IFN resistance during the course of the COVID-19 pandemic and to determine virus mutations and effector mechanisms involved. As interferon responses can regulate virus levels during the critical acute phase of infection, these studies will have implications for understanding SARS-CoV-2 transmission and pathogenesis that may inform therapeutic strategies not only against SARS- CoV-2 but also future emerging viruses.