Haematopoietic stem cells (HSCs) have high levels of exposure to stress stimuli owing to their long lifespan and they are more likely to undergo apoptosis in response to cellular stress than their downstream progenitors. This could help to prevent the propagation of damaged HSCs and to maintain the integrity of the haematopoietic cell population. The accumulation of misfolded proteins in the endoplasmic reticulum as a result of cellular stress activates the unfolded protein response (UPR), which comprises PERK, IRE1 and ATF6 pathways. Expression of PERK pathway constituents was greater in HSCs than in downstream progenitors, which resulted in preferential triggering of an apoptotic response to chemically induced stress. Human HSCs genetically engineered to have a decreased UPR had increased engraftment capacity compared with control HSCs when transplanted into immunodeficient mice, which indicates the in vivo relevance of the propensity of HSCs to undergo apoptosis.