<p>DNA replication is a fundamental cellular process that ensures the faithful duplication of the genome during cell division. However, this process is frequently challenged by various intrinsic and extrinsic factors that can impede replication fork progression and jeopardize genomic integrity. To safeguard against these challenges, cells have evolved intricate stress response mechanisms, including replication checkpoint activation, translesion DNA synthesis, repriming and fork reversal, all of which are vital for preserving genomic stability. Central to the orchestration of these pathways are post-translational modifications (PTMs), which dynamically regulate the stability, localization, and activity of key proteins involved in the replication stress responses. In this Review, we summarize the primary mechanisms that orchestrate cellular responses to replication stress and highlight emerging insights into the roles of both histone and nonhistone PTMs in the precise and coordinated regulation of replication fork dynamics under genotoxic conditions.</p><p></p>