Tissue-specific stem cells are the target for selected mutations in oncogenes or tumor suppressor genes that enhance the fitness of these cells, resulting in a self-limited clonal expansion and eventual cancer development. The initial or truncal mutations in the stem cell select for subsequent mutations that enhance their fitness, producing a reproducible order of mutations, selected for in each tissue type, during cancer development. Mutations in stem cells occur randomly, but the selection for increased fitness, occurs non-randomly, conferring a functional order on the selection of mutations. Tissue-specific stem cells are “units of natural selection” for somatic stem cells throughout life. This is why inherited cancer-causing mutations, which, by definition, are initial or truncal mutations, are observed to cause cancers with limited tissue specificities, even though the mutations are present in stem cells for all tissue types. In future studies, we need to understand why the same signal transduction pathways function differently in different tissue-specific stem cells. We also need to understand the truncal mutations for each cancer type, so as to eradicate the stem cell clones for that cancer before they produce a malignant tumor. To accomplish these objectives, we need to carry out new kinds of clinical trials with drugs that target mutations in tissue-specific stem cells.