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The mechanisms by which the p53 tumor suppressor acts remain incompletely understood. To gain new insights into p53 biology we used high throughput sequencing to analyze global p53 transcriptional networks in primary mouse embryo fibroblasts in response to DNA damage. Chromatin immunoprecipitation sequencing reveals 4785 p53 bound sites in the genome located near 3193 genes involved in diverse biological processes. RNA sequencing analysis shows that only a subset of p53 bound genes is transcriptionally regulated yielding a list of 432 p53 bound and regulated genes. Interestingly we identify a host of autophagy genes as direct p53 target genes. While the autophagy program is regulated predominantly by p53 the p53 family members p63 and p73 contribute to activation of this autophagy gene network. Induction of autophagy genes in response to p53 activation is associated with enhanced autophagy in diverse settings and depends on p53 transcriptional activity. While p53 induced autophagy does not affect cell cycle arrest in response to DNA damage it is important for both robust p53 dependent apoptosis triggered by DNA damage and transformation suppression by p53. Together our data highlight an intimate connection between p53 and autophagy through a vast transcriptional network and indicate that autophagy contributes to p53 dependent apoptosis and cancer suppression. © 2013 by Cold Spring Harbor Laboratory Press.