The description and interpretation of genomic abnormalities in cancer cells have been at the heart of cancer research for more than a century. With exhaustive sequencing of cancer genomes across a wide range of human tumors well under way, we are now entering the end game of this mission. In the forthcoming decade, essentially complete catalogs of somatic mutations will be generated for tens of thousands of human cancers. Here, I provide an overview of what these efforts have revealed to date about the origin and behavioral features of cancer cells and how this genomic information is being exploited to improve diagnosis and therapy of the disease.