Cancers are rare because their evolution is actively restrained by a range of tumour suppressors. Of these p53 seems unusually crucial as either it or its attendant upstream or downstream pathways are inactivated in virtually all cancers. p53 is an evolutionarily ancient coordinator of metazoan stress responses. Its role in tumour suppression is likely to be a relatively recent adaptation, which is only necessary when large, long-lived organisms acquired the sufficient size and somatic regenerative capacity to necessitate specific mechanisms to reign in rogue proliferating cells. However, such evolutionary reappropriation of this venerable transcription factor entails compromises that restrict its efficacy as a tumour suppressor.