p53, the "guardian of the genome" and the most mutated gene in cancer presents a considerable therapeutic opportunity as well as a challenge. In the past decade, several therapeutic strategies have been developed that aim to take advantage of a wealth of knowledge about p53, including insights into the biology and patho-biology of p53. Nevertheless, considerable challenges remain, not least as a result of tissue- and cancer-specific differences in p53 regulation and/or function. p53 does not act in the same manner in all tissues or in the cancers arising from them. Nor is p53 regulated in the same way in the wide variety of tissues from which cancers develop. Therefore, potential strategies for therapeutic targeting need to be tailored to each tumour/tissue type. This review summarises some of these tissue- and cancer-specific issues to suggest how different strategies are required for cancers arising from different tissues and to illustrate the complexities of therapeutic targeting of p53.