The law of natural selection can be used to understand cancer development at the level of species as well as at the level of cells and tissues. Through this perspective, I seek to explain: (i) Why the lack of sufficient selective pressure to prevent cancers in old age helps explain the exponential increase in cancer incidence in the elderly. (ii) Why the evolution of long-lived animals necessitated the acquisition of potent tumor suppressive mechanisms. (iii) How the requirement to prevent inappropriate somatic cell expansion and cancer has constrained developmental and tissue architectural modalities. (iv) How the evolution of well-adapted stem cells with complex niche requirements has conferred resistance to oncogenic mutations, as phenotype-altering genetic change is almost always disadvantageous within a well-adapted cell population. (v) How the impairment of stem cell fitness, as occurs in old age, can promote selection for adaptive mutations and cancer initiation. (vi) Why differential maintenance of stem cell fitness may explain how different vertebrate species with enormous differences in life span and body size similarly avoid cancer through reproductive years.