Bcl-2 proteins, characterized by up to four Bcl-2 homology domains (BH1-BH4), are critical regulators of the mitochondrial proapoptotic pathway. Three major subgroups have been described, namely antiapoptotic proteins, proapoptotic multidomain and BH3-only proteins. These are basic for present models explaining the regulation of the mitochondrial outer membrane permeability. However, several Bcl-2 proteins have been described that do not fit into these models, due to their atypical domain structure or due to their ability to induce apoptosis independently of BH3. These proteins are indicators for new mechanisms in apoptosis control by Bcl-2 proteins, which may supply additional targets for novel therapeutic approaches.