Contrasting direct and indirect activation models for Bax and Bak. (a) In the direct model (Letai et al., 2002), the putative activators Bim and tBid bind directly to Bax and Bak to drive their activation, whereas the sensitizers only bind to the pro-survival Bcl-2 homologs (‘Bcl-2 et al.’) via the BH3 domain (red triangle). (b) In the indirect activation model (Chen et al., 2005; Willis et al., 2005, 2007), the BH3-only proteins activate Bax and Bak not by binding to them directly, but instead by engaging the multiple pro-survival proteins that guard Bax and Bak. In this model, Bim and tBid are more potent than Bad and other BH3-only proteins owing to the greater range of pro-survival proteins that they can engage and neutralize.