A tightly controlled balance between cell survival and cell death assures correct development and normal physiology of multicellular organisms. Members of the Bcl-2 family that regulate apoptosis often control this decision between cell death and survival. The generation of gene-deficient mice has greatly aided our understanding of the function of most individual Bcl-2 family members. However, a function for Bcl2A1 (A1) has been elusive until the Herold group recently generated A1-deficient mice, filling a long-awaited gap. Their initial characterization is now reported in two papers in this issue of Cell Death & Differentiation. 1, 2

Bcl-2 proteins come in three flavors that have antiapoptotic or proapoptotic function (Figure 1). The proapoptotic group is further divided into BH3-only proteins (‘activators’ and ‘sensitizers’) as well as non-BH3-only ‘executioners’. Enhanced expression and/or post-transcriptional modification empowers ‘activators’(Bim, Puma, tBid and Bad) to induce a conformational change in ‘executioners’(Bax and Bak) to polymerize on the surface of mitochondria, thereby creating holes in the outer membrane and allowing cytochrome c (cyto c) to escape from the intermembrane space. In the cytoplasm, cyto c initiates the formation of high-molecularweight scaffolds to activate dormant caspases, which catalyze proteolytic intracellular disintegration. Destruction of the cell culminates in the formation of apoptotic bodies that are engulfed by macrophages. Antiapoptotic Bcl-2 proteins like Bcl-2, Mcl-1, Bcl-XL and A1, also known as ‘guardians’, interfere with the induction of apoptosis by binding and thereby neutralizing the proapoptotic members (Figure 1). However, being more than just a balance between pro-and antiapoptotic Bcl-2 family members, it is becoming quite clear that specific interactions between particular anti-and proapoptotic Bcl-2 family members regulate apoptosis. 3 Finally, sensitizers like Noxa tune the system by sequestering the guardians, thereby enhancing the threshold for apoptosis induction. Thus, regulated induction of apoptosis–dictated by specific