SummaryThe molecular mechanisms allowing hair follicles to periodically activate their stem cells (HFSCs) are incompletely characterized. Here, we identify the transcription factor IRX5 as a promoter of HFSC activation.Irx5−/−mice have delayed anagen onset, with increased DNA damage and diminished HFSC proliferation. Open chromatin regions form near cell cycle progression and DNA damage repair genes inIrx5−/−HFSCs. DNA damage repair factor BRCA1 is an IRX5 downstream target. Inhibition of FGF kinase signaling partially rescues the anagen delay inIrx5−/−mice, suggesting that theIrx5−/−HFSC quiescent phenotype is partly due to failure to suppressFgf18expression. Interfollicular epidermal stem cells also show decreased proliferation and increased DNA damage inIrx5−/−mice. Consistent with a role for IRX5 as a promoter of DNA damage repair, we find that IRX genes are upregulated in many cancer types and that there is a correlation betweenIRX5andBRCA1expression in breast cancer.