During tumour development cells sustain mutations that disrupt normal mechanisms controlling proliferation. Remarkably, the Rb-E2f and MDM2-p53 pathways are both defective in most, if not all, human tumours, which underscores the crucial role of these pathways in regulating cell cycle progression and viability. A simple interpretation of the observation that both pathways are deregulated is that they function independently in the control of cell fate. However, a large body of evidence indicates that, in addition to their independent effects on cell fate, there is extensive crosstalk between these two pathways, and specifically between the transcription factors E2F1 and p53, which influences vital cellular decisions. This Review discusses the molecular mechanisms that underlie the intricate interactions between E2f and p53.