This review discusses the immunomodulatory functions of type I interferons (IFNs), which are primarily known for their antiviral properties but also play crucial roles in host defense and homeostasis. The authors highlight the regulation of innate and adaptive immune responses, the response to bacterial ligands, inflammasome activation, intestinal homeostasis, and inflammatory and autoimmune diseases. They detail the signaling pathways activated by type I IFNs, including JAK-STAT, MAPK, and PI3K, and their roles in modulating immune responses. The review also explores the complex roles of type I IFNs in bacterial infections, autoimmune diseases such as multiple sclerosis and psoriasis, and cancer. The authors emphasize the need for a better understanding of the underlying pathophysiology to design effective treatments using type I IFNs or their neutralizing antibodies.This review discusses the immunomodulatory functions of type I interferons (IFNs), which are primarily known for their antiviral properties but also play crucial roles in host defense and homeostasis. The authors highlight the regulation of innate and adaptive immune responses, the response to bacterial ligands, inflammasome activation, intestinal homeostasis, and inflammatory and autoimmune diseases. They detail the signaling pathways activated by type I IFNs, including JAK-STAT, MAPK, and PI3K, and their roles in modulating immune responses. The review also explores the complex roles of type I IFNs in bacterial infections, autoimmune diseases such as multiple sclerosis and psoriasis, and cancer. The authors emphasize the need for a better understanding of the underlying pathophysiology to design effective treatments using type I IFNs or their neutralizing antibodies.