The tumor suppressor p53 plays a central role in the DNA damage response. After exposure to genotoxic stress, p53 can both positively and negatively regulate cell fate. Initially, p53 promotes cell survival by inducing cell cycle arrest, DNA repair, and other pro-survival pathways. However, when cells accumulate DNA damage or demonstrate aberrant growth, p53 can direct the elimination of damaged cells. In this review, we will discuss the transcriptional-dependent and -independent roles of p53 in regulating the DNA damage response.