The critical role of p53 tumor suppressors in limiting the generation of iPSC by induction of apoptosis or cell cycle arrest. Cell reprogramming is a stressful process accompanied with generation of ROS, induction of senescence, and DNA damage response. Activation of p53 and its downstream p21 observed during reprogramming is likely induced by DNA damage response. p21 is a cyclin-dependent kinase (CDK) inhibitor that regulates cell cycle arrest. Besides, senescence-induced expressions of p16 and p19 indirectly activate tumor suppressors p53 and Rb, respectively, leading to cell cycle arrest and apoptosis. Oct4-dependent activation of caspase 8 and 3 has a dual role in promoting apoptosis and cleavage of Rb, which favors reprogramming. Treatment of cells with Vitamin C also facilitates iPSC formation by scavenging ROS and meanwhile regulates histone demethylases Jhdm1a/1b, the latter of which is able to promote cell cycle progression and suppress senescence by repressing the Ink4/Arf locus. Double arrows: multiple steps.