The study investigates the factors influencing the efficiency and kinetics of reprogramming somatic cells into induced pluripotent stem (iPS) cells. The authors found that the reprogramming potential of primary fibroblasts decreases with serial passaging and senescence, suggesting that loss of replicative potential is a barrier for reprogramming. They demonstrate that cells with low endogenous ARF levels and immortal fibroblasts deficient for components of the p16INK4a/ARF/p53 pathway yield iPS colonies with faster kinetics and higher efficiency compared to wild-type (WT) cells. Additionally, acute genetic ablation of p53 in subpopulations that normally fail to reprogram rescues their ability to produce iPS cells. The results indicate that the acquisition of immortality is a crucial and rate-limiting step in the establishment of a pluripotent state in somatic cells, highlighting similarities between pluripotent cell lines and tumor cells.The study investigates the factors influencing the efficiency and kinetics of reprogramming somatic cells into induced pluripotent stem (iPS) cells. The authors found that the reprogramming potential of primary fibroblasts decreases with serial passaging and senescence, suggesting that loss of replicative potential is a barrier for reprogramming. They demonstrate that cells with low endogenous ARF levels and immortal fibroblasts deficient for components of the p16INK4a/ARF/p53 pathway yield iPS colonies with faster kinetics and higher efficiency compared to wild-type (WT) cells. Additionally, acute genetic ablation of p53 in subpopulations that normally fail to reprogram rescues their ability to produce iPS cells. The results indicate that the acquisition of immortality is a crucial and rate-limiting step in the establishment of a pluripotent state in somatic cells, highlighting similarities between pluripotent cell lines and tumor cells.