Bcl-2 family members are the arbiters of mitochondrial apoptotic pathway, which is conserved through evolution. The stoichiometry of pro- versus antiapoptotic Bcl-2 family members in the cell determines whether the cell lives or dies. This fine balance is regulated at the transcriptional or posttranslational level in response to various cellular cues. These signals are transmitted 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.