It is well accepted today that cancer develops through a multi-step process that involves normal cells being led by well-defined phases into cancer cells. Along this process cells lose their natural cancer defence system that is mediated by tumour suppressor genes and accumulate genetic instabilities that permit the expression of the specific oncogenic networks. Remarkable is the p53 tumour suppressor which is mutated in more than 50% of human cancers. In turn, various mutant p53 proteins with an oncogenic activity are accumulated in the cells and contribute to malignancy. This chapter overviews the p53 field with respect to the history behind the discovery of the p53 tumour suppressor, the structure and function of p53, the oncogenic activities of the various p53 mutants and the clinical significance of a tailor-made p53-based gene therapy.