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Complete duplication of large metazoan chromosomes requires thousands of potential initiation sites, only a small fraction of which are selected in each cell cycle. Assembly of the replication machinery is highly conserved and tightly regulated during the cell cycle, but the sites of initiation are highly flexible, and their temporal order of firing is regulated at the level of large-scale multi-replicon domains. Importantly, the number of replication forks must be quickly adjusted in response to replication stress to prevent genome instability. Here we argue that large genomes are divided into domains for exactly this reason. Once established, domain structure abrogates the need for precise initiation sites and creates a scaffold for the evolution of other chromosome functions.