The cellular response to DNA damage is a crucial surveillance mechanism that maintains genomic integrity and prevents cancer progression. Previous studies identified multiple Ser/Thr protein kinases that have pivotal roles in the activation of this response. It is interesting that a growing body of evidence suggests that these kinases and their substrates are under tight modulation by numerous Ser/Thr phosphatases. In this study, we review recent reports that reveal new functions and regulation of these phosphatases. Similar to the kinases in this pathway, phosphatases may also be intimately involved in cancer progression and present valuable targets for cancer therapy.