Loss of tumour suppressor function is a common mechanistic step in deregulated cell growth and neoplasia. The p53 tumour suppressor gene is the most frequently mutated gene in cancer, and is inactivated in approximately 50% of human tumours. Mutation of p53 is also the predominant molecular basis of the Li-Fraumeni familial cancer susceptibility syndrome. p53 is a transcription factor that functions to regulate the integrity of the genome in response to DNA damage by inducing genes that promote cell cycle arrest, cell death, or repair of damaged DNA. These various effects exerted by p53 ensure that mutations do not pass on to subsequent generations, thus avoiding the presence of cells with multiple genetic hits that predispose the cell to neoplastic growth. Analysis of p53 functions using genetically-modified mice has complimented studies performed with human cancer tissue or cultured cells, and has greatly expanded knowledge about the role of p53 in tumour suppression. This finer understanding of p53 function has greatly facilitated research into small-molecule and other drug modifications of p53 activity as treatment modalities for the many human cancers bearing altered p53 function. This review will examine mouse models containing p53 modifications, and access the contribution of these studies to the understanding of p53-mediated tumour suppression.