The activation of oncogenes occured in most tumors, and is believed to play an important role in tumorigenesis. However, the activation of oncogenes could induce cellular senescence in wild type cells, known as oncogene-induced senescence (OIS). Thus, the activation of oncogenes has the dual role in inducing cellular senescence or tumorigenesis. DNA damage checkpoint response (DDR) is the molecular signal transduction pathway that delay or arrest cell cycle progression in response to DNA damage and is an important molecular mechanism that induce cellular senescence. Activation of oncogenes could produce DNA damage signals and initiate DDR, which subsequently induce cellular senescence. However, when DDR pathway is deficient, activation of oncogenes could induce unlimited DNA hyper-replication and cellular hyper-proliferation, which results in accumulation of genome instability, and tumorigenesis ultimately. Therefore, the dual role of activated oncogenes is regulated by the integrity of DDR pathway. The key role of DDR in regulating activated oncogenes indicates that maintain or restore the integrity of DDR pathway might provide a new strategy in cancer prevention and therapy.