Technical Abstract: As a major step toward understanding the biology and evolution of ruminants, the cattle genome was sequenced to ~7x coverage using a combined whole genome shotgun and BAC skim approach. The cattle genome contains a minimum of 22,000 genes, with a core set of 14,345 orthologs found in seven mammalian species. Evolutionary breakpoint regions in chromosomes that are cattle-specific have a higher density of segmental duplications, several types of repetitive elements, and species-specific variations in genes associated with lactation and immune responsiveness. Genes involved in metabolism were found highly conserved, although five metabolic genes are deleted or extensively diverged from their human counterparts. The cattle genome sequence provides a new resource for mammalian genome annotation and for accelerating genetic improvement for milk and meat production.