Loss of the G1/S checkpoint is recognized as a mandatory step in the development of cancer. Nevertheless, both in vivo and in vitro experiments have indicated that this condition highly sensitizes cells to apoptosis, e.g., primary mouse embryonic fibroblasts that lack the complete retinoblastoma suppressor gene family (TKO MEFs) massively die under mitogen-deprived conditions. The prevailing hypothesis therefore is that the increased proliferative capacity of cells that have lost the G1/S checkpoint becomes apparent by suppression of apoptosis. However, this view was recently challenged by the finding that suppression of apoptotic cell death in TKO MEFs did not allow unconstrained proliferation; instead, cells became arrested in G2. This mechanism, which is dependent on p53, provides yet another barrier to oncogenic transformation. Thus, progression to malignancy of Rb-deficient lesions by alleviation of G2 arrest may offer an alternative explanation for the synergism between loss of Rb and p53 in tumorigenesis.