Interferon classes are distinguished by the unique complimentary receptor complexes through which they signal. IFNα, and other type 1 interferons (IFNs), engage through the IFNα receptor complex, composed of IFNαR1 and IFNαR2, while IFNλ signals through the IL-28RA and IL-10R2 complex. Despite triggering distinct receptor complexes, the downstream signaling of both IFNα and IFNλ is regulated through JAK/STAT signal transduction, ultimately resulting in the induction of IFN-stimulated response elements (ISRE) and initiation of gene transcription. Opposed to the ubiquitously expressed IFNα receptor, the IFNλ receptor appears to be more limited in its expression. IRF, interferon regulatory factor; ISGF, interferon-stimulated gene factor; JAK, Janus kinase; STAT, signal transducers and activators of transcription; TYK, tyrosine.