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Abstract Hypoxia, a characteristic of most human solid tumors, is a major obstacle to successful radiotherapy. While moderate acute hypoxia increases cell survival, chronic cycling hypoxia triggers adaptation processes, leading to the clonal selection of hypoxia-tolerant, apoptosis-resistant cancer cells. Our results demonstrate that exposure to acute and adaptation to chronic cycling hypoxia alters the balance of Bcl-2 family proteins in favor of anti-apoptotic family members, thereby elevating the apoptotic threshold and attenuating the success of radiotherapy. Of note, inhibition of Bcl-2 and Bcl-xL by BH3-mimetic ABT-263 enhanced the sensitivity of HCT116 colon cancer and NCI-H460 lung cancer cells to the cytotoxic action of ionizing radiation. Importantly, we observed this effect not only in normoxia, but also in severe hypoxia to a similar or even higher extent. ABT-263 furthermore enhanced the response of xenograft tumors of control and hypoxia-selected NCI-H460 cells to radiotherapy, thereby confirming the beneficial effect of combined treatment in vivo. Targeting the Bcl-2 rheostat with ABT-263, therefore, is a particularly promising approach to overcome radioresistance of cancer cells exposed to acute or chronic hypoxia with intermittent reoxygenation. Moreover, we found intrinsic as well as ABT-263- and irradiation-induced regulation of Bcl-2 family members to determine therapy sensitivity. In this context, we identified Mcl-1 as a resistance factor that interfered with apoptosis induction by ABT-263, ionizing radiation, and combinatorial treatment. Collectively, our findings provide novel insights into the molecular determinants of hypoxia-mediated resistance to apoptosis and radiotherapy and a rationale for future therapies of hypoxic and hypoxia-selected tumor cell fractions.