P53 is a transcription factor that can cause cells to be eliminated by apoptosis or senescent-like arrest upon its activation by irreparable genetic damage, excessively expressed oncogenes, or a broad spectrum of other stresses. As P53 executes life and death decisions, its activity must be stringently regulated, which implies that it is not likely to be controlled by a simple regulatory mechanism involving a binary on-off switch. This brief review will summarize a subset of the new information presented at the 10th P53 workshop in Dunedin, New Zealand in November 2004 as well as very recent publications that provide new insights into the molecular regulators of P53. Data emerging from mouse models provide a fundamentally different view of how P53 is regulated than suggested by more traditional in vitro approaches. The differences between cell culture and mouse models demonstrate the importance of preserving stoichiometric relationships between P53 and its various regulators to obtain an accurate view of the relevant molecular mechanisms that control P53 activity.