The study investigates the functional and physical interaction between Beclin-1, an essential autophagy gene, and Bcl-2, a paradigmatic apoptosis-inhibitory protein. Beclin-1 is identified as containing a BH3-like domain that interacts with the BH3 receptor regions of Bcl-2 and Bcl-XL. This interaction is disrupted by BH3-only proteins and BH3 mimetics, leading to increased autophagic activity. The BH3-like domain of Beclin-1 is phylogenetically conserved and can induce apoptosis in a Bax-dependent manner. The BH3 mimetic ABT737 inhibits the interaction between Beclin-1 and anti-apoptotic Bcl-2 proteins, stimulating autophagy without inducing apoptosis. Overexpression of Beclin-1 enhances autophagy, which is further increased by ABT737. The BH3-only protein Bad also modulates autophagy induction during starvation. In C. elegans, the BH3-only protein EGL-1 is sufficient to trigger autophagy, demonstrating the phylogenetic conservation of this mechanism. These findings reveal a novel function of the BH3-binding site of Bcl-2 homologs in regulating autophagy, highlighting the crosstalk between apoptosis and autophagy.The study investigates the functional and physical interaction between Beclin-1, an essential autophagy gene, and Bcl-2, a paradigmatic apoptosis-inhibitory protein. Beclin-1 is identified as containing a BH3-like domain that interacts with the BH3 receptor regions of Bcl-2 and Bcl-XL. This interaction is disrupted by BH3-only proteins and BH3 mimetics, leading to increased autophagic activity. The BH3-like domain of Beclin-1 is phylogenetically conserved and can induce apoptosis in a Bax-dependent manner. The BH3 mimetic ABT737 inhibits the interaction between Beclin-1 and anti-apoptotic Bcl-2 proteins, stimulating autophagy without inducing apoptosis. Overexpression of Beclin-1 enhances autophagy, which is further increased by ABT737. The BH3-only protein Bad also modulates autophagy induction during starvation. In C. elegans, the BH3-only protein EGL-1 is sufficient to trigger autophagy, demonstrating the phylogenetic conservation of this mechanism. These findings reveal a novel function of the BH3-binding site of Bcl-2 homologs in regulating autophagy, highlighting the crosstalk between apoptosis and autophagy.