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The TP53 tumor suppressor gene and its protein product p53, play a critical role in the cellular stress response. Upon exposure to stressors, such as DNA damage, oncogene activation, or perturbations to the ribosome biogenesis, p53 is activated and is capable of inducing cell cycle arrest, apoptosis, or senescence via the transactivation of genes such as p21, Noxa, Bax, Puma, and GADD45. While p53 expression, and activity, is integral to the cellular stress response, overexpression of p53 is inhibitory to embryonic development, illustrating the importance of proper p53 regulation. Growing evidence has implicated the nucleolus, as well as nucleolar proteins, in the regulation of both p53 and its primary negative regulator Mdm2. The role of nucleolar proteins, including ARF, B23/NPM, and ribosomal proteins, in mediating the p53 stress response serves to link the cell cycle progression and protein synthesis, and suggests p53 is a common regulator capable of coordinating these processes to best maintain the genetic integrity of the cell.