Cellular responses to hypertonic stress and how these are linked to the induction of or sensitisation to cell death signals are incompletely understood and rarely studied in cancer. Using cell lines derived from head and neck squamous cell carcinoma (HNSCC), Heimer et al. demonstrate that hypertonic environments neutralise the antiapoptotic Bcl‐2 family member Mcl‐1 by upregulating its antagonist Noxa. Consequently, hypertonically stressed HNSCC cells rely solely on Bcl‐xL for survival and succumb to apoptosis when challenged by pharmacological Bcl‐xL inhibition. Similar findings were reported in colorectal cancer cells in related manuscripts, suggesting that a common and conserved mechanistic link might exist between hyperosmotic stress and cellular sensitisation to apoptosis.