Abstract: Apoptosis is an evolutionarily conserved process for killing unwanted cells. Genetic and biochemical experiments have indicated that three groups of proteins are necessary for activation of the cell‐death effector machinery: cysteine proteases, their adaptors, and proapoptotic Bcl‐2 family members. Antiapoptotic Bcl‐2 family members are needed for cell survival. We have cloned Bim, a proapoptotic Bcl‐2 family member that shares with the family only a 9‐16 aa region of homology [Bcl‐3 homology region (BH3)], but is otherwise unique. Bim requires its BH3 region for binding to Bcl‐2 and activation of apoptosis. Analysis of Bim‐deficient mice has shown that Bim is essential for the execution of some but not all apoptotic stimuli that can be antagonized by Bcl‐2. Bim‐deficient mice have increased numbers of lymphocytes, plasma cells, and myeloid cells, and most develop fatal autoimmune glomerulonephritis. In healthy cells, Bim is bound to the microtubule‐associated dynein motor complex, and is thereby sequestered from Bcl‐2. Certain apoptotic signals unleash Bim and allow it to translocate to intracellular membranes, where it interacts with Bcl‐2 or its homologues. These results indicate that BH3‐only proteins are essential inducers of apoptosis that can be unleashed by certain death signals. Unleashed BH3‐only proteins neutralize the prosurvival function of Bcl‐2‐like molecules, and this is thought to liberate Apaf‐l‐like adapters to activate caspase zymogens, which then initiate cell degradation.