Laboratory mice have represented a powerful experimental system for understanding the intricacy of human cancer pathogenesis. Indeed, much of our current conceptualization of how tumorigenesis occurs in humans is strongly influenced by mouse models of cancer development. However, an emerging body of evidence indicates that there are fundamental differences in how the process of tumorigenesis occurs in mice and humans. What are these species-specific differences and how do they affect the use of mice as models of human tumour pathogenesis?