Bcl-2 family members are the arbiters of mitochondrial apo- ptotic pathway, which is conserved through evolution. The stoi- chiometry of pro- versus antiapoptotic Bcl-2 family members in the cell determines whether the cell lives or dies. This fine bal- ance is regulated at the transcriptional or posttranslational level in response to various cellular cues. These signals are transmit- ted through the upstream molecules in the pathway, that is, the BH3-only molecules that results in the activation of the adaptor molecules, Bax and Bak, at the mitochondrial surface ensuing mitochondrial dysfunction and apoptosis. Understanding the activation process offers a great potential in the therapeutic intervention of many diseases such as cancer and autoimmune disorders.