In response to cellular stress, p53 acts as a transcription factor by binding as a tetramer to diverse DNA targets, thereby activating the expression of genes involved in cell-cycle arrest or apoptosis. The loss of p53 activity as a result of specific mutations is a critical event in cancer development. We elucidated the crystal structures of the core domain of human p53 bound to different DNA targets, the structure of the free protein and of several oncogenic mutants. The comparative analysis of the various proteins provides a structural framework for understanding the mechanisms of DNA recognition by p53 and the deleterious effects of specific mutations on this function.