Cancer cell plasticity, whereby stem-cell-like properties are attained in response to stress, represents a major challenge in cancer treatment. Using cell line and patient-derived xenograft (PDX) models, we report that translational reprogramming which occurs in response to stresses such as hypoxia and chemotherapy engenders stem cell properties in breast cancer. Breast cancer stem cell (BCSC)-associated genes such as NANOG, SNAIL and NODAL manifest multiple isoforms characterized by different 5’ Untranslated Regions (5’UTRs), a subset of which is translationally activated under stress when global protein synthesis is reduced. We demonstrate that these mRNAs are translationally induced by mTOR suppression and concomitant up-regulation in eIF2α phosphorylation, and that such translational reprogramming underpins BCSC phenotypes such as self-renewal and epithelial-mesenchymal transition. Accordingly, we demonstrate that mTOR inhibitors induce stem cell phenotypes in breast cancer, partially explaining their lower-than-expected clinical efficacy. Most notably, we report that stress-induced BCSC phenotypes can be overcome with drugs that antagonize the effects of eIF2α phosphorylation and increase ternary complex recycling (e.g. ISRIB). Indeed, studies conducted using cell lines and PDX models indicate that ISRIB decreases BCSCs in hypoxic tumours and increases the efficacy of mTOR inhibitors and chemotherapies by suppressing breast cancer plasticity.