The accidental discovery of the mouse polyoma virus nearly 50 years ago opened up an experimental system unique in opportunities for investigating virus-host interactions leading to the development of tumors. Extensive studies of the virus in tissue culture have provided a detailed understanding of its genetics and molecular biology. Knowledge of the virus as a transforming agent in culture can now be tested in the animal where multiple cell types are targets for tumorigenic conversion and where a variety of host factors, both immunological and nonimmunological, come into play. Studies in the animal using well-characterized wild-type and mutant virus strains have led to some unexpected findings. Some of these run counter to certain widely held beliefs in cancer biology. This minireview focuses on these surprising findings and the challenges they raise. (C) 2001 Academic Press.