Initiation of DNA replication is a key control point in the mammalian cell cycle that often goes awry in cancer. During initiation, pre-replication complex proteins assemble at the origins of replication and recruit DNA polymerases and other proteins needed for DNA synthesis. Dawn Coverley and co-workers now report that p21Cip1-interacting zinc finger protein 1 (Ciz1) promotes DNA replication late in initiation, after the formation of pre-replication complexes (see p. 101). Using a cell-free system that allows them to reconstitute initiation of mammalian DNA replication, the authors show that Ciz1 increases the number of nuclei that initiate DNA replication. In intact cells, addition of Ciz1 stimulates DNA synthesis, even in a p21Cip1-null background, indicating that Ciz1 promotes DNA replication directly rather than by acting through modulation of p21Cip1 – a replication inhibitor. These and other observations, including the demonstration that RNAi-mediated depletion of Ciz1 inhibits entry into S phase, indicate that Ciz1 is at the heart of proliferation control in mammalian cells.