The fundamental biological role of DNA is to store genetic information. To perform that role, DNA is organized into genes, the basic units of inheritance, and genes are organized into genomes. In the last 75 years, we have solved the structure of DNA, discovered its role in the function of genes and sequenced the human genome. This chapter documents those breakthroughs and how they, and many other seminal discoveries, have elucidated the function of genes and genomes in the function of cells, the development of organisms and the evolution of species. Our knowledge of the mechanisms by which genomes are expressed, repaired, replicated, and packaged has vastly improved, with detailed biochemical understanding and many atomic-resolution structures of the protein machines that effect DNA metabolism. We now face the challenge of understanding how these myriad machines interact and are inter-regulated in the complex environment of the nucleus. For example, although we have a good idea how one promoter works, we only understand in the most general terms how thousands of promoters are regulated precisely both temporally and spatially, as organisms develop. Advances in realistic mechanistic explanations of the emergent properties of genomes in living cells will occupy the field for decades to come.