Apoptosis has classically been viewed as a process not involving mitochondria, whereas the implication of mitochondrial dysfunction in necrosis has been recognized for several decades. Recently, it has become clear that apoptosis implies a disruption of mitochondrial membrane intregrity that is decisive for the cell death process. Cytofluorometric methods assessing the mitochondrial membrane function and structure can be employed to demonstrate that, at least in most models of apoptosis, mitochondrial changes precede caspase and nuclease activation. Moreover, pharmacological and genetic experiments suggest that the loss of mitochondrial membrane integrity is a critical event of the apoptotic process, beyond or at the point of no return of programmed cell death. Inhibitors of the mitochondrial megachannel (= permeability transition pore) can prevent both the mitochondrial and the post-mitochondrial manifestations of apoptosis.