Interferons are divided into type I, II, and III. Type I IFNs (IFN-α and IFN-β) are most abundant in number, distribution, and expression. Also, they are highly conserved among mammals in both structure and function. IFN-α and IFN-β are potent antiviral cytokines that are produced after viral infections, which induce an antiviral state in neighboring cells by upregulating the transcription of IFN-stimulated genes. IFN-α is ubiquitously expressed; nevertheless, plasmacytoid dendritic cells are the main source of IFN-α in response to invading pathogens. Type I IFNs play a crucial role in dendritic cell maturation, B cell activation, priming of primary antibody responses, and memory CD8+ T cell proliferation, and to prolong long-term survival. IFN-α enhances TLR responsiveness in macrophages by up-regulating the expression of TLR3, TLR4, and TLR7. Thus, IFN-α regulates TLR-dependent gene expression of IFN-α, IFN-β, IL-28, and IL-29. IFN-α had been used in the treatment of chronic hepatitis C. Nevertheless, IFN-α is relatively unstable and requires frequent parenteral administration. Pegylation of IFN-α and polyethylene glycol (PEG)-IFN-α reduces in vitro activity, but increases the stability and plasma half-life of IFN-α. Therefore, PEG-IFN-α has replaced IFN-α in chronic hepatitis C treatment.