Normal and tumor cells subjected to a hypoxic microenvironment show evidence of autophagy. We hypothesize that cells will sense hypoxia as a warning signal to upcoming drastic microenvironmental conditions and that autophagy, acting as a survival mechanism, will provide time for cells to adapt. This work demonstrates for the first time that the atypical BH3-domain of BNIP3 and BNIP3L, two HIF-target genes, can compete with Beclin 1-Bcl-2 and Beclin 1-Bcl-X(L) complexes, releasing Beclin 1 from the complex and then enhancing autophagy. We thus revealed a new role for BH3-only proteins in the cellular response to hypoxia.