Abstract Cancer is a multistep process whereby genetic events that result in the activation of proto-oncogenes or the inactivation of tumor suppressor genes usurp physiologic programs mandating relentless proliferation and growth. Experimental evidence surprisingly illustrates that the inactivation of even a single oncogene can be sufficient to induce sustained tumor regression. These observations suggest the hypothesis that tumors become irrevocably addicted to the oncogenes that initiated tumorigenesis. The proposed explanation for this phenomenon is that activated oncogenes result in a signaling state in which the sudden abatement of oncogene activity balances towards proliferative arrest and apoptosis. Indeed, substantial evidence supports this hypothesis. Here, we propose an alternative, although not necessarily mutually exclusive, explanation for how oncogenes initiate and sustain tumorigenesis. We suggest that oncogene activation initiates tumorigenesis precisely because it directly overrides physiologic programs inducing a state of cellular amnesia, not only inducing relentless cellular proliferation, but also bypassing checkpoint mechanisms that are essential for cellular mortality, self-renewal, and genomic integrity. Because no single oncogenic lesion is sufficient to overcome all of these physiologic barriers, oncogenes are restrained from inducing tumorigenesis. Correspondingly, in a tumor that has acquired the complete complement of oncogenic lesions required to overcome all of these safety mechanisms, the inactivation of a single oncogene can restore some of these pathways resulting in proliferative arrest, differentiation, cellular senescence, and/or apoptosis. Thus, oncogenes induce cancer because they induce a cellular state of enforced oncogenic amnesia in which, only upon oncogene inactivation, the tumor becomes aware of its transgression. [Cancer Res 2008;68(9):3081–6]