The subject invention pertains to agonist peptides of type I interferons and methods of using the peptides. These peptides are based on the amino acid sequence of the C-terminus region of the type I IFN molecules and are capable of binding to the cytoplasmic domain of type I IFN receptors. Surprisingly, these peptides were found to possess the same or similar biological activity as that associated with the full-length, mature type I IFN proteins, even though these peptides do not bind to the extracellular domain of the type I IFN receptors. In one embodiment, the peptide is a peptide of IFNα. In another embodiment, the peptide is a peptide of IFNβ. Exemplified peptides of the invention include those having SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:38, SEQ ID NO:39, and SEQ ID NO:40. The subject peptides have been shown to effect increased resistance to viral infection. Peptides of the invention can be used to treat or prevent viral infections, to treat oncological disorders, and to treat autoimmune disorders, such as multiple sclerosis.