Cell proliferation demands that identical genetic material is passed to daughter cells that form during mitosis. Genetic copies are produced during the preceding interphase, when DNA of the mother cell is copied exactly once. While few processes in biology are regulated with this precision, the fundamental importance cannot be understated as defects might compromise genetic integrity and ultimately lead to cancer. Replication of the human genome in diploid cells occurs during S phase of the cell cycle. Throughout this ~10h period, about 10% of replication units - replicons - are active at any time, even though all potential initiation sites - origins - are established before the onset of S phase. Crucially, the mechanisms that regulate origin selection and define a structured replication programme remain to be defined. We review recent progress in understanding the structure and regulation of S phase and develop a model that we believe best describes the S phase programme in human cells.