This review develops the concept of p53 as a transcription factor mediating growth arrest or cell death in response to long-term (senescence-related) as well as acute (DNA damage) signals. Evidence is presented to support the importance of both functions in tumour development. The role of p53 in senescence is discussed in the context of the telomere theory and in relation to its more established function as a 'guardian of the genome'. Finally, data indicating important tissue-specific differences in the control of proliferative life-span by p53 are reviewed, together with potential clinical implications.