Early work by Shogen and Yoon1 demonstrated an anti-tumor activity in extracts of Northern leopard frog (Rana pipiens) embryos. More than a decade later, in 1987, the main active component of those extracts was isolated and purified by Alfacell M. It turned out to be a small (approximately 12 Kd) basic protein of maternal origin (present also in large amounts in unfertilized oocytes). Its complete amino acid sequence was determined in our laboratory and was found to be unique.2 Surprisingly, the sequence was similar to those of pancreatic ribonuclease A (RNase A, EC 3.1.27.5) and other members of the RNase A superfamily. All 3 catalytic residues of RNase A were conserved as were some of the other residues forming the active site and/or the hydrophobic core.2,3 Thus, the protein seemed to be fully equipped to exert ribonucleolytic activity, and indeed was found capable of degrading highly polymerized RNA from yeast and wheat germ, although the reaction rates were distinctly lower that those of other pancreatic-type ribonucleases.2 It was also cytostatic and cytotoxic to several cancer cell lines in vitro including human submaxillary carcinoma A-253,2,4 and significantly increased the survival of mice bearing M109 Madison Carcinoma5. As we discuss later in this article, the protein also posses strong anti viral activity. We provisionally named the molecule P-30 Protein and later changed the name to Onconase (ONC). In addition to ONC, extracts of Rana pipiens oocytes, contain its natural variant, different by 3 amino acid residues6 and at least 4 variants of a novel cytotoxic ribonuclease, amphinase, recently discovered and sequenced in our laboratory.7 In this article, we discuss the structure and function of ONC as well as therapeutic potential of this enzyme with particular emphasis on its anti viral activity.