Time matters: circadian genetics and the molecular logic of human health and disease

Time is an essential but often underappreciated determinant of human physiology and disease. The circadian clock, a genetic timing system, orchestrates transcriptional and signalling networks across tissues to maintain homeostasis. Recent discoveries have refined our understanding of this system, from a linear transcription-translation feedback loop to a distributed, dynamically coupled network that integrates environmental cues and physiological processes. Genetic variation in core circadian genes and circadian misalignment are now recognized as key modifiers of disease risk, progression and therapeutic response. As precision medicine begins to embrace temporal biology, defining how the circadian clock operates in health and disease has become increasingly important. This Review synthesizes recent advances in circadian genetics and molecular mechanisms, emphasizing their physiological, pathological and therapeutic implications, and outlines future priorities: resolving the composition of the molecular clock, developing disease-specific models, and expanding the chemical toolbox to modulate and interrogate circadian pathways.