Genomes are intricate complexes of proteins and nucleic acids. The double-stranded DNA that makes up a chromosome is long in fully extended form, and the length far exceeds the cell’s dimensions. DNA-associated proteins assist this long piece of DNA to fold precisely to accommodate it within the cell or nucleus. Folded structures play a pivotal role in the regulation of gene expression. The folded structure differs in different domains of life and even within organisms of the same domain. This chapter describes the characteristics of folded genomes in three domains of life. The folded structure is not static. It changes in response to external signals or in synchrony with cellular events. Another aspect of the genomes is their DNA sequence changes over evolutionary time scales. Interestingly, more modest changes in sequence also occur over cellular and organismal generations. These changes are essential for evolution but may engender many pathological conditions. We describe molecular mechanisms that are responsible for the alteration of DNA sequence.