||In every cell division cycle, daughter cells carry the same genomic information as their parental cell. Maintenance of the genomic stability requires several checkpoints that function at different stages of the cell cycle. These checkpoints halt cell cycle progression to allow cells to have the time to correct errors. Cells with defective checkpoints may allow errors to accumulate and eventually promote tumorigenesis. Therefore, identifying components of the checkpoints is important for a better understanding of how genome stability is maintained. Protein phosphorylation is important in many cellular processes, including normal cell cycle progression and checkpoint regulation. While protein kinases involved in cell cycle control and checkpoints have been studied extensively, the protein phosphatases involving in the processes are less understood. To identify novel phosphatases important for mitosis and replicative stress responses, RNA interference screens targeting the all phosphatases in the human genome were performed. A short-hairpin RNA library against the human phosphatome was generated. These screens were designed to identify phosphatases that, when depleted, affected mitotic progression and survival after replicative stress. A large number of phosphatases were identified to be required for proper mitotic progression. Several phosphatases, including the non-receptor type protein tyrosine phosphatase PTPN11 (SHP2), were identified to be important for survival after replicative stress. Cells were more susceptible to hydroxyurea-induced cell death in the absence of SHP2. Furthermore, SHP2 is required for cell survival after other DNA damaging agents, indicating that SHP2 is critical for different DNA stresses. Collectively, these studies underscore the importance of protein phosphatases in cell cycle control.