Whereas early stages of embryogenesis are driven by maternal gene products, transcription of the zygotic genome is required to direct later events. Initiation of the embryo's transcription program occurs just before gastrulation at the midblastula transition (MBT) and is accompanied by changes in cell-cycle length, checkpoint activation and the onset of cell motility required for morphogenesis. It has long been thought that these events are triggered when the embryo attains a threshold nuclear/cytoplasmic (N/C) ratio, and an unknown, titratable factor becomes limiting through its interactions with the increasing DNA content. Now, Zegerman and colleagues show that four factors that control the rate of DNA replication initiation at high N/C ratios determine the onset of MBT events in Xenopus. Replication initiation requires both cyclin-dependent kinase (CDK) and Dbf4-dependent kinase (DDK) to activate replisomes in S phase. The authors show that levels of DDK subunit Drf1, CDK substrates Recq4 and Treslin and their interaction partner Cut5 decline during early cell divisions and become limiting for replication of sperm nuclei in Xenopus egg extracts and for replication initiation in fertilized eggs. Co-overexpression of these four factors shortens the cell-cycle length, producing embryos with increased cell numbers and DNA content after MBT, and causes earlier activation of the checkpoint kinase Chk1. This effect is reversible and dose dependent, consistent with a cell-cycle duration determined by replication-factor titration. Transcriptome sequencing of staged embryos reveals that the onset of zygotic gene expression is delayed upon overexpression of these replication factors, suggesting that transcription initiation at MBT is also controlled by cell-cycle length. Embryos overexpressing Drf1, Recq4, Treslin and Cut5 fail to complete gastrulation and die before neurula stage. However, limiting replisome assembly by depleting Cdc6 suppresses lethality, indicating that the developmental defects associated with factor overexpression are the result of changes in replication initiation frequency. These studies suggest that titration of key DNA-replication factors can promote the cell-cycle changes that control MBT events. (Science doi:10.1126/science.1241530, published online 1 August 2013)