Abl is a ubiquitously expressed nonreceptor tyrosine kinase that is involved in diverse cellular signaling cascades. The cellular response mediated by Abl depends upon its subcellular localization. Expression of Abl in the cytoplasm results in cell proliferation and survival. In contrast, nuclear Abl is activated and induces apoptosis after genotoxic stress. Recent studies have demonstrated the molecular mechanisms by which c-Abl moves into the nucleus in the response to DNA damage. In normal cells, 14-3-3 proteins sequester c-Abl in the cytosol. Upon exposure of cells to genotoxic agents, c-jun N-terminal kinase is activated and phosphorylates 14-3-3, resulting in the release of c-Abl into the nucleus. Moreover, nuclear targeting of c-Abl is required for the induction of apoptosis in response to DNA-damaging agents. Thus, c-Abl may determine cell fate via its subcellular localization. This review summarizes the implications of these findings on our understanding of Abl-regulated cellular functions and potential therapeutic strategies to modulate the aberrant kinase.