The transcription-in dependent p53-mediated apoptotic response has obtained a solid mechanistic basis in recent years. A fraction of stress-induced wild type p53 protein rapidly translocates to mitochondria in response to genotoxic, hypoxic, and oxidative stresses in established cell lines and primary cells, as well as in physiological and pathophysiologic stress responses in the animal. While the groundwork of mechanisms and kinetics of direct mitochondrial p53 activities is laid out, the quantitative contribution of this pathway to total p53-mediated apoptosis and tumor suppression in vivo remains to be elucidated. An update on these efforts is given here. © 2005 Elsevier Inc. All rights reserved.