Systemic Sclerosis (Scleroderma, SSc) is an autoimmune disease characterized by vasculopathy, inflammation, and fibrosis that can lead to loss of organ function. Type I interferons (IFNs) are family of cytokines that mitigate the deleterious effects of viral and bacterial infections in the innate immunity system. Past several years, research efforts have been focused on the role of type I IFN and IFN-inducible genes in the pathogenesis of SSc. Polymorphisms in the Interferon regulatory factor (IRF)-5, IRF7, and IRF8 are associated with SSc, Similarly, polymorphism of Signal Transducer and Activator of Transcription (STAT)-4, has been established as a genetic risk factor of SSc. IRFs and STAT4 proteins are key activators of type I IFN signaling pathways. An IFN signature (increased expression and activation of IFN-regulated genes) has been observed in the peripheral blood and skin biopsy samples of patients with SSc. Furthermore, a plasma IFN-inducible chemokine score correlated with markers of disease severity and autoantibody subtypes in SSc. In this review, we summarize our current knowledge of the role of type I IFNs and IFN-inducible genes in the pathogenesis of SSc and their potential role as biomarkers and therapeutic targets.