In humans, more than 6 billion bp of DNA need to be copied accurately and completely every cell division. Given the size of human chromosomes, it would take a pair of bidirectional DNA replication forks, emanating from a single replication origin, more than 40 days to copy just chromosome 1. To duplicate the genome completely within the confines of S-phase, multiple start sites of DNA replication need to be distributed across each of the chromosomes. Understanding how start sites of DNA replication are selected and regulated across a diverse array of cell types has been a major question in the field since the discovery of the double helix. In PNAS, Miotto et al. describe the genome-wide localization of a key replication initiation factor, the origin recognition complex (ORC), and provide insight into the genomic features that define the location and distribution of human replication origins.