p53 is a critical mediator of cellular responses to a variety of stresses. Given the frequency of p53 mutations in human malignancies and that disruption of p53 has been implicated in chemoresistance, understanding the factors that select for p53 disruption is important both for understanding tumor evolution and for designing cancer therapies. While it is widely believed that genotoxic stress selects for p53 mutations, the effects of DNA damaging agents on long-term proliferative potential are usually not affected by p53 status. Previous reports have demonstrated that despite being activated, p53 loss does not prevent cell cycle arrest and senescence in response to high levels of acute replicational stress. In contrast, we recently reported that chronic exposure of non-transformed cells to low, clinically relevant levels of replicational stress induces p53-dependent senescence-like arrest. Disruption of p53 or its target gene p21(CIP1) antagonizes this arrest, leading to a long-term proliferative advantage. However, when replicational stress is associated with substantial DNA strand breaks, the ability of p53 disruption to up-regulate RAD51 dependent homologous recombination becomes important. Replicational stress is induced by many chemotherapeutic treatments and perhaps by some dietary deficiencies, and may be an important factor that selects for p53 mutations during cancer initiation and progression.