Heat-shock protein (HSP) genes are activated by the heat-shock factor 1 (HSF1) as a defence mechanism against physiological stress. In addition, other cellular alterations can occur during this protective response; for instance, the levels of reactive oxygen species (ROS), which are mainly produced in mitochondria, have been shown to correlate with the heat-shock response (HSR) in several different systems, but their role therein is still not fully understood. Now, Subramaniam Ganesh and Saloni Agarwal (Agarwal and Ganesh, 2020) show that perinuclear clustering of mitochondria is essential for the HSR in mammalian cells. This specific, but also transient, mitochondrial dynamics occurs when cells are subjected to a mild heat shock and is microtubule- and kinesin-1-dependent. The redistribution of mitochondria triggers an ROS increase in both the perinuclear and nuclear areas, which results in DNA oxidation. In addition, mitochondrial clustering and elevated ROS also control the initiation of the HSR by activating HSF1. Most importantly, the authors demonstrate that HSF1 activation is dependent on the hypoxia inducible factor-1α (HIF-1α), whose transcription increases during the HSR. Altogether, this study establishes the importance of mitochondrial dynamics and its relationship with the hypoxia response pathway in eliciting the HSR.