RB1 (retinoblastoma) was the first tumor-suppressor gene to be described and is often mutated in many human cancers. Its product, Rb protein, is well known for its negative regulation of the cell cycle and, more recently, for its accessory role in chromatin remodeling. Julien Sage, Marius Wernig and colleagues investigated the function of Rb in reprogramming, leading to new insights into tumorigenesis (Cell Stem Cell 16, 39–50, 2015). They discovered that inactivating Rb facilitates reprogramming of fibroblasts to a pluripotent state. Surprisingly, their data indicate that this does not involve interference with the cell cycle but instead that Rb directly binds to and represses pluripotency-associated loci such as Oct4 (Pou5f1) and Sox2. Loss of Rb seems to compensate for the omission of Sox2 from the cocktail of reprogramming factors. Furthermore, genetic disruption of Sox2 precludes tumor formation in mice lacking functional Rb protein. This study positions Rb as a repressor of the pluripotency gene regulatory network and suggests that loss of Rb might clear the path for Sox2, or other master regulators of stem cell identity, to induce cancer. It will be interesting to analyze the potential role of Rb in other types of in vitro reprogramming.