DNA damage has been shown to regulate DNA replication both by inhibition of origin utilization, and by slowing of replication progression. We have recently reported another mechanism by which DNA damage affects replication, in which the presence of damaged DNA inhibits, in trans, the initiation of chromosomal replication. This inhibition occurs by blocking the association of the processivity clamp PCNA with undamaged chromatin. This inhibitory activity is not due to sequestration of replication factors by the damaged DNA, rather, it acts through generation of a diffusible inhibitor of PCNA loading. The activation of this pathway is independent of canonical checkpoint signaling, and, in fact, results in activation of the checkpoint. This novel pathway may therefore represent an amplification step to stop cell cycle progression in response to lower levels of DNA damage.