Molecular checkpoints stop cells with genetic lesions from proliferating and spreading. Classical tumor suppressors, such as p53, exert pleiotropic effects on the cell cycle and apoptosis in response to DNA damage signals. It has been hypothesized that an unidentified checkpoint regulates stem cell self-renewal in adult tissues. Now, Lenhard Rudolph and colleagues report that the basic leucine zipper transcription factor BATF acts as a checkpoint factor for hematopoietic stem cell (HSC) self-renewal (Cell 148, 1001–1014, 2012 ). In an RNA interference screen, they found that mouse HSCs depleted of Batf continued contributing to hematopoiesis, despite having shortened telomeres, an aging-associated DNA lesion. Batf deletion or knockdown also improved HSC self-renewal in response to other types of DNA damage, such as g-irradiation, although DNA breaks accumulated in these HSCs. Conversely, Batf expression was upregulated during aging or DNA damage in a cytokine signaling–dependent manner. Upregulation of Batf impaired HSC renewal, drove differentiation toward the lymphoid lineage and activated the classical tumor suppressor checkpoint proteins p53 and p21. In human HSCs isolated from individuals with myelodysplastic syndrome, BATF levels were positively correlated with expression of the cell cycle inhibitor CDKN1A and negatively correlated with telomere length.