This review provides an overview of interferon-stimulated genes (ISGs) and their roles in host defense against pathogens. Interferons (IFNs) are produced by cells in response to pathogen detection, initiating a signaling cascade through the JAK-STAT pathway, which leads to the transcription of hundreds of ISGs. These genes play a crucial role in enhancing pathogen detection, regulating innate immune signaling, and controlling viral, bacterial, and parasitic infections. The review highlights how ISGs both enhance and modulate the IFN signaling pathway, with some ISGs directly inhibiting virus infection at early and late stages of the viral life cycle. Key ISGs such as Myxovirus resistance (Mx), Cholesterol-25-hydroxylase (CH25H), and TRIM proteins are discussed in detail, along with their mechanisms of action. The review also explores the role of ISGs in IFN desensitization, which is important for preventing autoimmune disorders, and the ongoing efforts to identify and characterize new antiviral ISGs. Finally, it discusses the potential of ISG-based therapies and the impact of contemporary technologies on our understanding of ISG biology.This review provides an overview of interferon-stimulated genes (ISGs) and their roles in host defense against pathogens. Interferons (IFNs) are produced by cells in response to pathogen detection, initiating a signaling cascade through the JAK-STAT pathway, which leads to the transcription of hundreds of ISGs. These genes play a crucial role in enhancing pathogen detection, regulating innate immune signaling, and controlling viral, bacterial, and parasitic infections. The review highlights how ISGs both enhance and modulate the IFN signaling pathway, with some ISGs directly inhibiting virus infection at early and late stages of the viral life cycle. Key ISGs such as Myxovirus resistance (Mx), Cholesterol-25-hydroxylase (CH25H), and TRIM proteins are discussed in detail, along with their mechanisms of action. The review also explores the role of ISGs in IFN desensitization, which is important for preventing autoimmune disorders, and the ongoing efforts to identify and characterize new antiviral ISGs. Finally, it discusses the potential of ISG-based therapies and the impact of contemporary technologies on our understanding of ISG biology.