Interferons (IFN) are pleiotropic cytokines essential for defense against infection, but the identity and tissue distribution of IFN-responsive cells in vivo are poorly defined. In this study, we generate a mouse strain capable of reporting IFN-signaling activated by all three types of IFNs and investigate the spatio-temporal dynamics and identity of IFN-responding cells following IFN injection and influenza virus infection. Despite ubiquitous expression of IFN receptors, cellular responses to IFNs are highly heterogenous in vivo and are determined by anatomical site, cell type, cellular preference to individual IFNs, and activation status. Unexpectedly, type I and II pneumocytes, the primary target of influenza infection, exhibit striking differences in the strength and temporal dynamics of IFN signaling associated with differential susceptibility to the viral infection. Our findings suggest that time- and cell-type-dependent integration of distinct IFN signals govern the specificity and magnitude of IFN responses in vivo. Display omitted •M1Red mouse reports on cellular responses to all three types of interferons (IFNs)•Hematopoietic progenitors and myeloid cells highly respond to IFN stimulation•Respiratory influenza virus infection induces local and systemic IFN signaling•Influenza-susceptible pneumocytes respond poorly to IFNs early during infection Stifter et al. generated an Irgm1 reporter mouse sensitive to induction by all three types of IFNs. They show that cellular responses to IFNs are highly heterogenous in vivo. Furthermore, different types of IFNs act in a cell-type-dependent manner to convey synergistic, antagonistic, or non-redundant signaling during influenza infection.