The cellular response to a variety of stress including DNA damage is involved in cell cycle arrest, activation of DNA repair, and in the event of irreparable damage, induction of apoptosis. However, the signals that determine cell fate, that is, survival or apoptosis, are largely unknown. Accumulating studies have revealed that dual-specificity tyrosine-regulated kinases (DYRKs) play key roles on cell proliferation and apoptosis induction. In particular, DYRK2 translocates from the cytoplasm into the nucleus following genotoxic stress. DYRK2 is then activated by ATM and induce apoptosis by phosphorylating p53 at Ser46. Importantly, whereas precise regulation of these kinases remain uncertain, this mechanism has consequences for cell proliferation, differentiation, or apoptosis. This progress review highlights recent efforts demonstrating that DYRKs could be novel and essential regulatory molecules for the regulation of cell fate including apoptosis.