Mitochondria play a critical role in apoptosis, or programmed cell death, by releasing apoptogenic factors from the intermembrane space. This process, known as mitochondrial outer membrane permeabilization (MOMP), is tightly regulated by the Bcl-2 family proteins. Pro-apoptotic Bcl-2 family members, Bax and Bak, change their conformation when activated by BH3 domain-only proteins in the family and permeabilize the MOM, whereas pro-survival members inhibit permeabilization. The precise nature of the apoptotic pore in the MOM is unknown, but is probably lipidic. Furthermore, it has been realized that there is another layer of MOMP regulation by a protein factor termed the catalyst in the MOM in order for Bax/Bak to achieve efficient and complete membrane permeabilization. Mitochondrial dynamics do not affect MOMP directly, but seem closely coordinated with MOMP for swift protein efflux from mitochondria. This review will present current views on the molecular mechanisms and regulation of MOMP and conclude with recent developments in clinical applications based on the knowledge gleaned from the investigation. J. Cell. Biochem. 115: 632–640, 2014. © 2013 Wiley Periodicals, Inc.