Reactive oxygen species (ROS) generated by endogenous and exogenous agents cause DNA damage and activation of DNA damage response (DDR). DDR activation arrests the cell cycle progression to repair DNA lesions and activate a program encoding ROS-sensitive proteins involved in DDR. ATM, ATR, DNA-PKs, AMPK, Chk1, and Chk2 represent the sensors and transducers that coordinate DDR. Their signals converge on effectors, as tumor suppressor p53, Cdc25 protein phosphatase, and WEE1 tyrosine kinase. DNA repair pathways occur by several DNA repair enzymes such as DNA glycosylases, PARP1, AP endonuclease, ERCC1, MLH, and MSH. DDR triggers apoptosis or necrosis when the DNA damage cannot be repaired. DDR-targeted proteins, whose inhibitors are currently in clinical trials, are indicated in bold. snc-RNAs = small noncoding RNAs; lnc-RNAs = long noncoding RNAs; ATM = ataxia telangiectasia-mutated protein; ATR = ATM- and Rad3-related; AMPK = AMP-activated protein kinase; CDK = cyclin-dependent kinase; DNA-PKcs = dependent protein kinase catalytic subunit; PLK1 = polo-like kinase 1; WIP1 = wild-type p53-induced protein 1; PARP = poly (ADP-ribose) polymerase; AP endonuclease = apurinic/apyrimidinic endonuclease; MLH = MutL homolog; MSH = MutS homolog.