Pluripotent stem cells (PSCs) harbor constitutive DNA replication stress during their rapid proliferation and theconsequent genome instability hampers their applications in regenerative medicine. It is therefore important to un-derstand the regulatory mechanisms of replication stress response in PSCs. Here, we report that mouse embryonicstem cells (ESCs) are superior to differentiated cells in resolving replication stress. Specifically, ESCs utilize a uniqueFilia-Floped protein complex-dependent mechanism to efficiently promote the restart of stalled replication forks,therefore maintaining genomic stability. The ESC-specific Filia-Floped complex resides on replication forks undernormal conditions. Replication stress stimulates their recruitment to stalling forks and the serine 151 residue of Filiais phosphorylated in an ATR-dependent manner. This modification enables the Filia-Floped complex to act as a func-tional scaffold, which then promotes the stalling fork restart through a dual mechanism: both enhancing recruitmentof the replication fork restart protein, Blm, and stimulating ATR kinase activation. In the Blm pathway, the scaffoldsrecruit the E3 ubiquitin ligase, Trim25, to the stalled replication forks, and in turn Trim25 tethers and concentratesBlm at stalled replication forks through ubiquitination. In differentiated cells, the recruitment of the Trim25-Blmcomplex to replication forks and the activation of ATR signaling are much less robust due to lack of the ESC-specificFilia-Floped scaffold. Thus, our study reveals that ESCs utilize an additional and unique regulatory layer to efficient-ly promote the stalled fork restart and maintain genomic stability.