Cellular senescence is characterized by a largely irreversible cell cycle arrest that can be triggered by many types of intrinsic and extrinsic stress. These include telomere malfunction, oncogene activation and tumor suppressor gene inactivation. Ultimately, such events culminate in the activation of a tumor suppressor gene network. Since the first description of Oncogene-Induced cellular Senescence (OIS) little over a decade ago, many subsequent studies have confirmed that OIS prevents cells from undergoing oncogenic transformation in vitro. However, it has long been debated whether any in vivo correlates exist. It is only since recent years that evidence has been accumulating indicating that OIS in vivo does correspond to a major protective mechanism against cancer. In this review, we highlight some of the recent developments.