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Reactive oxygen species (ROS) at the right concentration promote cell proliferation in cell culture, stem cells, and model organisms. However, the mystery of how ROS signaling is coordinated with cell cycle progression and integrated into the cell cycle control machinery on the molecular level remains unsolved. Here, we report increasing levels of mitochondrial ROS during the cell cycle in human cell lines that target cyclin-dependent kinase 2 (CDK2). Chemical and metabolic interferences with ROS production decrease T-loop phosphorylation on CDK2 and so impede its full activation and thus its efficient DNA replication. ROS regulate CDK2 activity through the oxidation of a conserved cysteine residue near the T-loop, which prevents the binding of the T-loop phosphatase KAP. Together, our data reveal how mitochondrial metabolism is coupled with DNA replication and cell cycle progression via ROS, thereby demonstrating how KAP activity toward CDKs can be cell cycle regulated. [Display omitted] • Mitochondrial ROS drive cell cycle progression and proliferation • Cyclin-dependent kinase 2 (CDK2) is increasingly oxidized during the cell cycle • The oxidation state of a conserved cysteine on CDK2 regulates KAP binding • CDK2 oxidation promotes T-loop phosphorylation and DNA replication Reactive oxygen species (ROS) are by-products of mitochondrial respiration. Kirova et al. find that mitochondrial ROS increase during the cell cycle and oxidize cyclin-dependent kinase 2 (CDK2) to regulate its interaction with KAP phosphatase. CDK2 oxidation promotes T-loop phosphorylation and the CDK2 activity needed for DNA replication and proliferation. [ABSTRACT FROM AUTHOR]