IFNs were first described as potent antiviral agents 40 years ago, and recombinant IFN-α_2a and IFN-α_2b were approved for the treatment of hairy cell leukemia just 11 years ago. Today, α-IFNs are approved worldwide for the treatment of a variety of malignancies and virologic diseases. Although the exact mechanism of action of IFN-α in the treatment of such diseases is not fully understood, many advances have been made in the characterization of the physicochemical and diverse biological properties of this highly pleiotropic cytokine. Here we review recent developments in our understanding of the antiviral and immunoregulatory properties of IFN-α, the nature of the multisubunit IFN-α receptor, and the molecular mechanisms of signal transduction. Where available, we have included comparative data on recombinant α-IFNs derived from both naturally occurring and nonnaturally occurring synthetic genes. We also review clinical data and data on the side effects and antigenicity of different sources of recombinant α-IFNs in humans. These latter topics are of clinical interest, because they may potentially affect the efficacy of these various products. Hopefully, what is already known about IFN will prompt further exploration into the mechanism(s) of action of IFN-α and thus deliver new applications for this prototypic cytokine, whose full therapeutic potential is yet to be realized.