Models of Bcl-2–family function at the mitochondrion during apoptosis. (A) The traditional simple rheostat model assumes that the antiapoptotic Bcl-2–family proteins antagonize the BH3-only proteins, in an equal and opposite manner. (B) Recent results suggest a more inclusive and detailed model, which we term the “switched rheostat.” Bax and Bak are the effectors of MOMP. Certain BH3-only proteins (“direct activators”) and p53 switch on Bax (and possibly Bak) directly and are antagonized by antiapoptotic Bcl-2–family proteins. Other BH3-only proteins (“derepressors”) do not activate Bax directly but act by antagonizing the antiapoptotic family members, thereby freeing the direct activators to trigger Bax/Bak–induced MOMP. The dashed lines indicate that the derepressor BH3-only proteins have differing specificities for antiapoptotic family members.