p53 acts as a hub for many stress signals in cells. Once being activated, p53 is stabilized and subject to post-translational modifications. It also recruits co-factors, binds to chromatin and activates hundreds of downstream targets that include both protein-coding and noncoding RNAs. These downstream targets will elicit various cellular outcomes, such as cell cycle arrest, apoptosis, senescence and stem cell differentiation. A new generation of genome-wide approaches, such as ChIP-seq and RNA-seq, can measure high quality signals of chromatin binding, cofactor recruitment, post-translational modifications and p53-regulated targets.