The ability of a eukaryotic cell to precisely and accurately replicate its DNA is crucial to
maintain genome stability. Here we describe our current understanding of the process by
which origins are licensed for DNA replication and review recent work suggesting that fork
stalling has exerted a strong selective pressure on the positioning of licensed origins. In light
of this, we discuss the complex and disparate phenotypes observed in mouse models and
humans patients that arise due to defects in replication licensing proteins.