Type I interferons (IFNs) play crucial roles in activating intracellular antimicrobial programs and modulating innate and adaptive immune responses. The canonical signaling pathway involves the activation of Janus kinase (JAK)–signal transducer and activator of transcription (STAT) proteins, leading to the transcription of interferon-stimulated genes (ISGs). Host, pathogen, and environmental factors regulate these responses, calibrating host defenses while limiting tissue damage and preventing autoimmunity. This review focuses on the mechanisms that regulate type I IFN-induced STAT activation and ISG transcription and translation, including basal signaling, augmentation, and suppression. These regulatory mechanisms determine the biological outcomes of type I IFN responses, whether pathogens are cleared effectively or chronic infection or autoimmune disease ensues. The review also discusses the role of type I IFNs in autoimmune diseases and chronic infections, highlighting the complex interplay between type I IFNs and other cytokines such as TNF. Understanding these regulatory mechanisms is essential for developing rational therapies that promote pathogen eradication and alleviate autoimmune diseases.Type I interferons (IFNs) play crucial roles in activating intracellular antimicrobial programs and modulating innate and adaptive immune responses. The canonical signaling pathway involves the activation of Janus kinase (JAK)–signal transducer and activator of transcription (STAT) proteins, leading to the transcription of interferon-stimulated genes (ISGs). Host, pathogen, and environmental factors regulate these responses, calibrating host defenses while limiting tissue damage and preventing autoimmunity. This review focuses on the mechanisms that regulate type I IFN-induced STAT activation and ISG transcription and translation, including basal signaling, augmentation, and suppression. These regulatory mechanisms determine the biological outcomes of type I IFN responses, whether pathogens are cleared effectively or chronic infection or autoimmune disease ensues. The review also discusses the role of type I IFNs in autoimmune diseases and chronic infections, highlighting the complex interplay between type I IFNs and other cytokines such as TNF. Understanding these regulatory mechanisms is essential for developing rational therapies that promote pathogen eradication and alleviate autoimmune diseases.