The story of SV40-induced tumorigenesis and cellular transformation is intimately entwined with the development of modern molecular biology. Because SV40 and other viruses have small genomes and are relatively easy to manipulate in the laboratory, they offered tractable systems for molecular analysis. Thus, many of the early efforts to understand how eukaryotes replicate their DNA, regulate expression of their genes, and translate mRNA were focused on viral systems. The discovery that SV40 induces tumors in certain laboratory animals and transforms many types of cultured cells offered the first opportunity to explore the molecular basis for cancer. The goal of this article is to highlight some of the experiments that have led to our current view of SV40-induced transformation and to provide some context as to how they contributed to basic research in molecular biology and to our understanding of cancer.