The p53 protein plays diverse, complementary roles in the regulation of cell proliferation, genetic integrity and survival after exposure to various forms of genotoxic and non-genotoxic stresses. While there is considerable in vivo evidence that induction of apoptosis in response to DNA damage is an important biological response mediated by p53, the physiological role of p53 in the control of the cell cycle is still poorly understood. In this review, we first discuss evidence showing that p53 expression, protein level and activity are regulated in a cell-cycle dependent manner (by transcriptional control, control of protein stability, and changes in phosphorylation, acetylation and protein conformation). We then summarize the data available on the direct or indirect involvement of p53 in the control of cell-cycle progression in G1, S, G2 and M phases. Based on recent in vitro and in vivo data, we suggest that permanent cell-cycle arrest may represent a response to stress in cells with limited proliferative potential, which allows both genetic and tissular integrity to be preserved. We also discuss the way in which cell-cycle regulation may contribute to control p53 protein levels and activity during the normal cell cycle.