A sophisticated network of BCL-2 family proteins regulates the mitochondria-associated (intrinsic) apoptosis pathway. Antiapoptotic members such as BCL-XL or MCL-1 safeguard the outer mitochondrial membrane and prevent accidental cell death in a functionally redundant and/or compensatory manner. However, BCL-XL/MCL-1-mediated "dual apoptosis protection" also impairs response of cancer cells to chemotherapy. Here, we show that hyperosmotic stress in the tumor environment abrogates dual BCL-XL/MCL-1 protection. Hypertonicity triggers upregulation of NOXA and loss of MCL-1 and thereby enforces exclusive BCL-XL addiction. Concomitant targeting of BCL-XL is sufficient to unlock the intrinsic apoptosis pathway in colorectal cancer cells. Functionally, "osmotic reprogramming" of the tumor environment grants contextual synthetic lethality to BCL-XL inhibitors in dually BCL-XL/MCL-1-protected cells. Generation of contextual synthetic lethality through modulation of the tumor environment could perspectively boost efficacy of anticancer drugs.