Evolutionary theory makes strong predictions about the nature and effectiveness of cancer suppression across different species, with size and longevity being critical parameters. In using this theory to increase our understanding of human cancers, we need to consider what it predicts about both interspecific and intraspecific patterns. Here I focus on two issues: using gene expression data to illustrate why the mouse model can be highly misleading in understanding human cancers due to phylogenetic separation and to the obvious differences in size and longevity; and using theoretical patterns of mutation-selection balance to provide insight into the possible role of novel pathogens or other environmental factors in driving the frequency of cancer.