Genome duplication is precisely regulated by cyclin-dependent kinases CDKs, which bring about the onset of S phase by activating replication origins and then prevent re-licensing of origins until mitosis is completed. The optimum sequence motif for CDK phosphorylation is S/T-P-K/R-K/R, and Drc1-Sld2 is found to have at least 11 potential phosphorylation sites. Drc1 is required for DNA synthesis and S-M replication checkpoint control. Drc1 associates with Cdc2 and is phosphorylated at the onset of S phase when Cdc2 is activated. Thus Cdc2 promotes DNA replication by phosphorylating Drc1 and regulating its association with Cut5. Sld2 and Sld3 represent the minimal set of S-CDK substrates required for DNA replication.