I will explore a sequence of discoveries that spanned three-quarters of a century and culminated in the realization that the seeds of cancer reside in our own genomes. Harold Varmus will then explain where that realization has taken us in the struggle to understand and control cancer. In 1911, Peyton Rous reported the discovery of a virus that can cause sarcomas in chickens. Disparaged by many and neglected for decades, Rous Sarcoma Virus (RSV) eventually emerged as a highly tractable experimental system with which to probe the secrets of the cancer cell. RSV posed two great puzzles: how might its RNA genome be replicated and stabilized in the host cell, and how does the virus convert cells to malignant behavior? The first puzzle was solved by the discovery of reverse transcriptase, an enzyme in the viral particle that copies RNA into DNA, which is then inserted into the host genome. The second puzzle was solved when the virus was found to have an “oncogene” (v-src) that encodes a protein tyrosine kinase. The fact that v-src plays no role in viral replication raised the possibility that the gene had not originated in concert with the remainder of the viral genome, but instead had been acquired by accident from an external source. That proved to be the case, when a virtually identical homologue of v-src (c-src) was found in avian and other vertebrate cells. By elaborate molecular gymnastics, a cellular gene (or “proto-oncogene”) had been copied into the viral genome, in the process suffering a mutation that created an oncogene. It soon became apparent that normal vertebrate cells contain a large variety of proto-oncogenes, perversions of which have been implicated in the genesis of human cancer. A first step had been taken towards the realization that all cancer arises from the malfunction of genes.