Abstract only In humans, loss of the fragile X mental retardation protein, FMRP, leads to the most common inherited form of intellectual disability, the fragile X syndrome. FMRP is predominantly present in the cytoplasm where it regulates translation of proteins important for synaptic function. However a small percentage of FMRP is localized in the nucleus where its function has remained unclear. We demonstrate that FMRP associates with chromatin and participates in the replication stress‐dependent DNA damage response (DDR), possibly by recognizing specific histone modifications. Taken together, our findings uncover an unexpected role of FMRP in the DDR and suggest that FMRP‐dependent maintenance of genomic stability may be a potential contributing factor in the development of the fragile X syndrome.