The BCL-2 family of proteins regulates apoptosis, and proper control of this process is required for normal development and for preventing disease (Adams 2003; Danial and Korsmeyer 2004). After years of identifying components and deciphering the regulatory pathways that control apoptosis, we are now at the point of exploiting this knowledge in sophisticated ways for therapeutic intervention in disease conditions such as cancer. Members of the BCL-2 family fall into three different classes of proteins based on conservation of BCL-2 homology (BH1–4) domains: multidomain anti-apoptotic proteins (BCL-2, BCL-xL, MCL-1, BCL-w, and BFL-1/A1), multidomain proapoptotic proteins (BAX and BAK), and BH3-only proapoptotic proteins (BID, BAD, BIM, PUMA, NOXA, HRK, BMF, and NBK/BIK). The proapoptotic BH3-only proteins are the most apical regulators of this death-signaling cascade, and are activated by multiple stimuli from inside or outside the cell to initiate the apoptotic response. They are regulated transcriptionally, and by post-translational modifications such as phosphorylation, ubiquitination, and proteolytic cleavage (Puthalakath and Strasser 2002). Their BH3 domain is an amphipathic α-helix that serves as a binding motif for interaction with a hydrophobic groove on either multidomain anti-or proapoptotic BCL-2 family members. This BH3 domain-mediated interaction of BH3-only proteins with multidomain BCL-2 family proteins either antagonizes the survival activity of anti-apoptotic proteins or activates proapoptotic BAX and BAK. Evidence suggests that antagonism of survival functions cooperates with activation of BAX or BAK for cell death (Cheng et al. 2001; Letai et al. 2002; Chen et al. 2005; Kuwana et al. 2005). It is clear that BH3-only proteins function upstream of BAX and BAK, which are for the most part functionally redundant and required for apoptosis: Deficiency in BAX and BAK renders the proapoptotic function of BH3-only proteins inactive and confers resistance to apoptosis induced by many diverse stimuli (Lindsten et al. 2000; Wei et al. 2001; Zong et al. 2001; Degenhardt et al. 2002a, b). Significant issues being addressed include how the multidomain anti-apoptotic proteins act to control proapoptotic proteins, how toxic BAX and BAK are kept in check in healthy cells, and the targets and specificity of the multiple BH3-only proteins. Willis et al.(2005) provide insight into the specificity of BH3-only proteins by showing that BAK is activated through its NOXA-dependent displacement from MCL-1, and that coordinate inactivation of BCL-xL by other BH3-only proteins is required for cell death. Thus, the binding specificity of the BH3 domains of BH3-only proteins for particular multidomain proapoptotic and anti-apoptotic BCl-2 family members can reveal important aspects of the regulation of cell death. Understanding this regulation and its specificity is essential for developing therapeutics for diseases where apoptosis control is aberrant, such as cancer.