The intrinsic pathway of caspase activation can be initiated in response to DNA damage, growth factor withdrawal, loss of contact with the extracellular matrix, or glucocorticoids. These conditions promote signaling pathways that lead to a loss in the integrity of the mitochondrial membrane and caspase activation. The Bcl-2 family comprises a group of structurally related proteins that play a fundamental role in the regulation of the intrinsic pathway by controlling mitochondrial membrane permeability and the release of the pro-apoptotic factor, cytochrome c. Bcl-2 proteins are grouped into three classes: those that inhibit apoptosis (Bcl-2, Bcl-xL, Bcl-w, Mcl-1, Bcl-10, and Bcl-2 related protein A1); those that promote apoptosis (BAK, Bax, Bcl-rambo, Bcl-xs, BOK/Mtd); and the pro-apoptotic BH3-only proteins that bind and regulate the anti-apoptotic Bcl-2 proteins (Bad, BID, Bik/Nbk, BIM, BLK, Bmf, Hrk/DP5). Bag-1, BNIP3, BNIP3L are Bcl-2-interacting proteins that are also involved in modulating apoptosis. The balance between pro- and anti-apoptotic family members determines whether or not a cell will undergo apoptosis. Bcl-2 and Bcl-xL inhibit apoptosis by binding to the pro-apoptotic Bax and BAK proteins. In healthy cells, BAD is phosphorylated and sequestered in the cytoplasm by the adapter protein, 14-3-3. When cytoplasmic levels of free Bad increase, Bcl-2 and Bcl-xL bind to Bad and release Bax and BAK. Bax and BAK, or processed forms of these proteins, can then insert into the mitochondrial membrane and cause the release of cytochrome c. Cleavage of BID as a result of caspase-8, or caspase-10 activation following death receptor ligation also promotes Bax/BAK-mediated release of cytochrome c.