The environmental complexity in which living organisms found themselves throughout evolution, most likely resulted in various encounters that would continuously challenge the organisms' ability to survive. Coping with this stress can prove energetically demanding and might require the proper coupling between mechanisms aimed at sensing external stimuli and cellular strategies geared at producing energy. In this issue of BioEssays, Lovejoy and Hogg hypothesize that preservation of this bifaceted coupling can be detected by the maintenance and evolution of stress response mechanisms (...) at the genomic, molecular and cellular levels. Through ancestry‐tracking, they identify a group of related G protein‐coupled receptor systems with intersecting stress‐modulating properties which might represent an essential part of a complex organism's coping mechanisms to stress, an attribute that they suspect may be affected in individuals suffering from mood disorders such as depression. (shrink)