Cellular senescence, a permanent cell cycle arrest, is considered a safeguard mechanism that may prevent aged or abnormal cells from further expansion. Although the term “replicative senescence” stands for the widely accepted model of a terminal growth arrest due to telomere attrition, the significance of “oncogene-inducible senescence” remained an issue of debate over the years. A number of recent studies now show the effect of this acute and telomere-independent form of senescence as a tumor-protective, fail-safe mechanism in vivo that shares conceptual and possibly therapeutic similarities with the genetically encoded apoptosis machinery. (Cancer Res 2006; 66(6): 2881-4)