An adequate response to a sudden temperature rise is crucial for cellular fitness and survival. While heat shock response (HSR) is well described in bacteria and eukaryotes, much less information is available for archaea, of which many characterized species are extremophiles thriving in habitats typified by large temperature gradients. Here, we describe known molecular aspects of archaeal heat shock proteins (HSPs) as key components of the protein homeostasis machinery and place this in a phylogenetic perspective with respect to bacterial and eukaryotic HSPs. Particular emphasis is placed on structure–function details of the archaeal thermosome, which is a major element of the HSR and of which subunit composition is altered in response to temperature changes. In contrast with the structural response, it is largely unclear how archaeal cells sense temperature fluctuations and which molecular mechanisms underlie the corresponding regulation. We frame this gap in knowledge by discussing emerging questions related to archaeal HSR and by proposing methodologies to address them. Additionally, as has been shown in bacteria and eukaryotes, HSR is expected to be relevant for the control of physiology and growth in various stress conditions beyond temperature stress. A better understanding of this essential cellular process in archaea will not only provide insights into the evolution of HSR and of its sensing and regulation, but also inspire the development of biotechnological applications, by enabling transfer of archaeal heat shock components to other biological systems and for the engineering of archaea as robust cell factories.

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