DNA replication is a highly regulated process during which the genetic information of the cell is duplicated. The replication machinery encounters many challenges that threaten the transmission of genetic information to daughter cells. The term “replication stress” encompasses the diverse ways that progression of the replisome may be hindered, slowed or completely stalled (reviewed in [1]). The inability to deal with these challenges in a timely manner destabilizes the genome, which can lead to diseases, such as cancer, hematopoietic stem cell failure, inappropriate innate immune responses, and aging. Targeting DNA replication and induction of replication stress response has also been a mainstay of cancer therapies. This review will discuss sources of replication stress that threaten the fidelity of DNA replication and the mechanisms that mammalian cells use to efficiently restart stalled replication. For mechanisms of replication fork restart in prokaryotes, we direct readers to the following reviews [2, 3].