Interferons are ubiquitous cytokines produced by all mononuclear cell types in response to infection by a DNA or RNA virus. There are three major classes of interferons: type I or nonimmune interferons consist chiefly of interferons alpha produced by leukocytes and of interferon beta produced by fibroblasts, although there are several other less important variants; type II or immune interferon is interferon gamma, which is mainly produced by NK cells and T cells; and type III consists of the lambda interferons. Each type is characterized by a specific receptor and signal transduction pathway. Toll-like receptors (TLRs) on the cell membrane and endosomes recognize viruses and other microorganisms. Binding of DNA or RNA to endosomal TLRs generates a signal whose transduction pathways lead to molecules capable of binding to genes for various interferons, interleukin-1, and TNF⍺. Interferons can stimulate or inhibit up to 300 different genes encoding proteins involved in antiviral defense mechanisms, inflammation, adaptive immunity, angiogenesis, and other processes. The properties of interferons are used to treat a number of viral infections (e.g., hepatitis B and hepatitis C), inflammatory diseases (interferon beta for multiple sclerosis and interferon gamma for systemic sclerosis), and malignancies. Overactivation of the interferon pathways has been demonstrated in patients with systemic lupus erythematosus. The result is a characteristic pattern of mRNA expression known as the interferon signature. Interferon overactivation is related to inadequate clearance of apoptotic particles with accumulation of apoptosis products (DNA-CpG motifs and U-RNA). Similar abnormalities have been found in patients with primary Sjögren’s syndrome, systemic sclerosis, and polymyositis, as well as in some cases of rheumatoid arthritis. Immunomodulation strategies designed to decrease interferon overactivity are being evaluated in patients with systemic lupus erythematosus.