Type I interferons (IFNs) include the IFN-alpha family of subtypes, IFN-beta, IFN-omega, IFN-tau, IFN-kappa, IFN-lambda, and IFN-zeta. IFN genes lack introns and encode secretory signal peptide sequences that are proteolytically cleaved prior to secretion from the cell. In contrast to the approximately 50% amino acid sequence identity among the human IFN-alpha subtypes, human IFN-alphas share approximately 22% identity with human IFN-beta and 37% identity with human IFN-omega. Many of the conserved residues among the type I IFNs are implicated in receptor recognition and structural integrity. This report provides an update on the gene annotations for the mouse and human IFN gene clusters on chromosome 4 and 9, respectively, with accompanying amino acid sequence alignments. Based on sequence identities, a phylogenic tree analysis for the different mammalian Type I IFNs is also presented, showing the high degree of relatedness among these IFNs. Notably, sequence alignment of the different human and mouse IFN promoter regions reveals different signature patterns for transcription factor binding sites, implying different inducers might differentially activate the transcription of the different IFNs.