Focusing on driver-gene mutations and the pathways they control has rendered complex cancer-genome landscapes intelligible. In solid tumors of adults, alterations in as few as three driver genes appear to suffice for a cell to evolve into an advanced cancer. Nearly 30 years ago, it was hypothesized that cancers result from sequential mutations in specific oncogenes and tumor-suppressor genes. 1 This hypothesis was based on experimental data from patients with colorectal cancers and inspired by models proposed by Armitage and Doll, Nowell, Knudson, and others. Those experimental data were rudimentary by today's standards. The sequence of all coding genes has now been determined for more than 22,000 cancers, and more than 3 million somatic mutations have been discovered. So has the sequential cancer gene hypothesis stood the test of time? Genomewide sequencing has provided some relevant insights. It has shown that . . .