Cancer begins as an encounter between a carcinogen and a gene. For skin cancers, "UV-signature" mutations identify key sunlight targets such as p53, Notch, and PTEN. But mutations are rare and the multiple-genetic-hit model of cancer requires several of them in the same cell. A control point is the clonal expansion of the first mutant cell to increase the target size for the second mutation. What drives clonal expansion? We find that clonal expansion is driven by physiology, not by adding mutations. One mechanism is the mutant's resistance to UV-induced apoptosis. UV also tilts a stochastic stem cell's choice between proliferating and differentiating, tipping it toward more proliferation. To trigger these events, special regions of the DNA such as active genes or telomeres are monitored for DNA photoproducts or are highly UV-sensitive. These results support the new evolutionary view of cancer, where a mutant gene's effect is not inexorable and autonomous but depends on the selection pressures coming from its surroundings.