Inactivation of p53 function is a common event in cancer. Approximately 50% of human tumours express mutant p53 and there is evidence that in others, including many childhood tumours, p53 function is impaired in other ways. These defects in p53 function may be due to the alteration of cellular factors that modulate p53 or to the expression of viral oncoproteins. Radiotherapy and many of the chemotherapeutic drugs currently used in cancer treatment are potent activators of p53. However, most of these therapies have a serious drawback, and that is the long-term consequences of their DNA damaging effects. Here, we review the discoveries in p53 research that are most significant to the development of new therapies based on the induction of the transcriptional activity of p53 in a non-genotoxic way and discuss the situations in which this type of approach may be most beneficial.