Every cell in the human body has most of the components of the apoptotic apparatus and is thus principally equipped to die by apoptosis. Situations of increased or decreased apoptosis contribute to many forms of human disease, making this pathway an attractive target of therapeutic intervention. The past few years have seen an enormous refinement in the understanding how apoptosis works on a molecular level and the role of mitochondria as a central element in apoptotic signal transduction has become obvious. Here, the authors consider the events that are critical in this mitochondrial pathway, in particular at mitochondria but also upstream and downstream. The authors' opinion is presented on the merits and feasibility of approaches that aim at treating disease by interfering with the mitochondrial apoptotic pathway.