Identification of small inhibitory RNAs and microRNA established that regulation of RNA metabolism plays an essential role in controlling intracellular biochemical processes. Interferons induce a number of RNA degradation enzymes involved in innate immunity by degrading viral RNAs. We cloned human polynucleotide phosphorylase (hPNPase^old-35), a type I interferon-inducible 3’-5’ exoribonuclease, as a transcript induced during terminal differentiation and senescence, two physiological processes marked by irreversible growth arrest. Our studies in the last four years show that hPNPase^old-35 plays an essential role in mediating IFN-mediated growth inhibition and its upregulation might mediate chronic inflammatory pathological processes during aging. The present review recaps these findings and provides a framework for the future understanding of the versatile functions of this interesting molecule.