Every time a cell divides it must ensure that its genetic information is accurately duplicated and distributed equally to the two daughter cells. This fundamental biological process is conserved throughout all kingdoms of life and relies on the correct and complete duplication of the DNA before a cell can divide and give rise to other cells or to multicellular organisms. Any mistakes in this process can result in genetic mutations or karyotype aberrations, which may lead to disease or even death. Whereas in prokaryotes the entire genome is replicated from a single origin, the increased genome size and complexity in mammals requires the spatio-temporal coordination of thousands of replication origins. Furthermore, this spatio-temporal order of genome replication changes throughout development and cellular differentiation. Here we present and discuss current knowledge on the control of DNA replication dynamics in mammals and the role of chromatin modifications in this basic biological process. © 2011 Landes Bioscience.