Programmed cell death (apoptosis) is crucial for embryogenesis and tissue homeostasis. Deregulated apoptosis leads to immunodeficiency, autoimmune disorders or cancer. The two main routes to apoptosis are the extrinsic and intrinsic (mitochondrial) pathways. Both involve caspase activation that leads to the cleavage of multiple intracellular substrates [1,9]. This review highlights recent advances in our understanding of the intrinsic pathway. We describe how BCL-2-family members preserve or disrupt mitochondrial integrity, the contribution of BH3-only proteins to this process, and the importance of cytotoxic factors released by the mitochondria. The growing evidence that the intrinsic pathway is crucial for tumourigenesis makes this an intriguing field. In particular, the finding that BCL-2 homologues are inhibited by BH3-only proteins may have future therapeutic applications.