Mitochondrial membrane permeabilization [MMP] constitutes an essential step of the intrinsic pathway leading to apoptosis. Several oncoproteins, tumor suppressor gene products, viral virulence factors and pharmacological agents modulate apoptosis via direct effects on mitochondria. This has far-reaching implications for the pathophysiology of several major diseases such as cancer, neurodegeneration, and AIDS. The detailed investigation of the mechanisms of MMP will hopefully lead to the discovery of suitable drug targets for therapeutic intervention on cell death control.