The tumor suppressor protein p53 is a transcription factor that plays a key role in the prevention of cancer development. In response to oncogenic or other stresses, the p53 protein is activated and regulates the expression of a variety of target genes, resulting in cell cycle arrest, senescence, or apoptosis. Mutation of the p53 gene is the most common genetic alteration in human cancer, affecting more than 50% of human tumors. Most of these mutations inactivate the DNA-binding domain of the protein. In this chapter, we describe the structure of the wild-type p53 protein and present structural and functional data that provide the molecular basis for understanding the effects of common cancer mutations. Further, we assess novel therapeutic strategies that aim to rescue the function of p53 cancer mutants.