The Bcl-2 protein family, which largely determines commitment to apoptosis, has central roles in tumorigenesis andchemoresistance. Its three factions of interacting proteins include the BH3-only proteins (eg, Bim, Puma, Bad, Noxa), whichtransduce diverse cytotoxic signals to the mammalian pro-survival proteins (Bcl-2, Bcl-x L, Bcl-w, Mcl-1, A-1), whereas Baxand Bak, when freed from pro-survival constraint, provoke the mitochondrial permeabilization that triggers apoptosis. Wehave discovered unexpected specificity in their interactions. Only Bim and Puma, which mediate multiple cytotoxic signals, engage all the pro-survival proteins. Noxa and Bad instead bind subsets and cooperate in killing, indicating that apoptosis requiresneutralization of different pro-survival subsets. Furthermore, Mcl-1 and Bcl-x L, but not Bcl-2, directly sequester Bakin healthy cells, and Bak is freed only when BH3-only proteins neutralize both its guards. BH3-only proteins such as Bim aretumor suppressors and mediate many of the cytotoxic signals from anticancer agents. Hence, compounds mimicking themmay prove valuable for therapy. Indeed, the recently described ABT-737 is a promising" BH3 mimetic" of Bad. We find that, like Bad, ABT-737 kills cells efficiently only if Mcl-1 is absent or down-regulated. Thus, manipulation of apoptosis by targetingthe Bcl-2 family has exciting potential for cancer treatment.