As genomic sequencing projects attempt ever more ambitious integration of genetic, molecular, and phenotypic information, a specialization of genomics has emerged, embodied in the subdiscipline of computational genomics. Models inherited from population genetics, phylogenetics, and human disease genetics merge with those from graph theory, statistics, signal processing, and computer science to provide a rich quantitative foundation for genomics that can only be realized with the aid of a computer. Unleashed on a rapidly increasing sample of the planet’s 10 30 organisms, these analyses will have an impact on diverse fields of science while providing an extraordinary new window into the story of life.