Recent studies based on next‐generation DNA sequencing have revealed that the female inactive X chromosome is replicated in a rapid, unorganized manner, and undergoes increased rates of mutation. These observations link the organization of DNA replication timing to gene regulation on one hand, and to the generation of mutations on the other hand. More generally, the exceptional biology of the inactive X chromosome highlights general principles of genome replication. Cells may control replication timing by a combination of intrinsic replication origin properties, local chromatin states and global levels of replication factors, leading to a functional separation between the activity of genes and their mutation. The organization of DNA replication through time: initiation from well‐defined chromosomal loci (replication origins), and efficient DNA synthesis supported by an abundance of elongation factors, give way to random initiation and sub‐optimal replication fork elongation as S phase proceeds.