Eukaryotic cells replicate their DNA and coordinate their response to DNA damage and replication blocks by activating appropriate repair processes, regulating recombination, chromatin assembly and chromosome partitioning. Replication forks stall at specific problematic genomic regions, and forks collapse unless protected by replication checkpoint proteins. These events have been associated with recombination and chromosomal rearrangements that lead to genomic instability and cancer development. The replication checkpoints, activated by the checkpoint signals generated by stalled forks, protect the stability of the fork until the replication can resume, regulate recombination pathways, and coordinate the mechanisms that promote replication restart and repair. Domain barriers make easier the topological problems posed by replicating DNA and confine the DNA lesions in manageable units. Here, we focus on the molecular mechanisms that control and promote the stability of replication forks and on the regulation of replication restart, and its coordination with chromatin structure and postreplicative repair.