The p53 tumour suppressor protein plays a crutial role in regulating cell growth and death in response to various types of cellular stress. The loss of its function is the most common event leading to the development of cancer. normal cells, p53 is present at low levels because the protein is rapidly degraded by the ubiquitin-mediated proteasome pathway following synthesis. Stress induced signals inhibit p53 degradation, leading to rapid stabilization and accumulation of p53 protein in the cell, and followed by p53 protein activation by mechanisms including phosphorylation and acetylation. The complexity of the pathways regulating p53 stabilization and activation, as well as possible p53 activation in response to small chemical compounds used in certain experimental anti-cancer therapy approaches, are discussed in this review.