In the healthy state, both circadian rhythm and mood are stable against perturbations, yet they are capable of adjusting to altered internal cues or ongoing changes in external conditions. The dual demands of stability and flexibility are met by the collective properties of complex neural networks. Disruption of this balance underlies both circadian rhythm abnormality and mood disorders. However, we do not fully understand the network properties that govern the crosstalk between the circadian system and mood regulation. This puzzle reflects (...) a challenge at the center of neurobiology, and its solution requires the successful integration of existing data across all levels of neural organization, from molecules, cells, circuits, network dynamics, to integrated mental function. This essay discusses several open questions confronting the cross‐level synthesis, and proposes that circadian regulation, and its role in mood, stands as a uniquely tractable system to study the causal mechanisms of neural adaptation.Also watch the Video Abstract.Editor's suggested further reading in BioEssays Major depressive disorder: A loss of circadian synchrony? Abstract. (shrink)