The engulfment of a proto-mitochondrion by a primitive unicellular organism gave rise to the first eukaryotic cell, and ever since, mitochondrial function has been a vital aspect of eukaryotic life. Under conditions of physiological stress, the mitochondrion is far from a passive bystander, instead playing a key role in signalling pathways and the cellular responses they elicit. In this thematic series of Extreme Physiology & Medicine, the role of the mitochondrion in the response to physiological stress will be considered anew, through research articles, reviews, viewpoints and methodology papers that aim to reposition the organelle as a key player in the human response to a wide range of extreme conditions.