The tumor suppressor p53 controls numerous downstream targets that can result in variable outcomes, including apoptosis, transient growth arrest, and sustained growth arrest or senescence. The activation of p53, followed by its ability to play multiple roles in the control of genomic integrity or the elimination of damaged or tumorigenic cells, is performed by a complex process of cross-talk orchestrated to occur in the different compartments of the cell. Controlling performance of the many roles of p53 is a goal of many research groups and the focus of this review.