DNA replication forks are subject to intricate surveillance and strict regulation by sophisticated cellular machinery. Such close regulation is necessary to ensure the accurate duplication of genetic information and to tackle the diverse endogenous and exogenous stresses that impede this process. Stalled replication forks are vulnerable to collapse, which is a major cause of genomic instability and carcinogenesis. Replication stress responses, which are organized via a series of coordinated molecular events, stabilize stalled replication forks and carry out fork reversal and restoration. DNA damage tolerance and repair pathways such as homologous recombination and Fanconi anemia also contribute to replication fork stabilization. The signaling network that mediates the transduction and interplay of these pathways is regulated by a series of post-translational modifications, including ubiquitination, which affects the activity, stability, and interactome of substrates. In particular, the ubiquitination of replication protein A and proliferating cell nuclear antigen at stalled replication forks promotes the recruitment of downstream regulators. In this review, we describe the ubiquitination-mediated signaling cascades that regulate replication fork progression and stabilization. In addition, we discuss the targeting of replication fork stability and ubiquitination system components as a potential therapeutic approach for the treatment of cancer.