Circadian rhythms have developed in all light-sensitive organisms, including humans, as a fundamental anticipatory mechanism that enables proactive adaptation to environmental changes. The circadian system is organized in a highly hierarchical manner, with clocks operative in most cells of the body ensuring the temporal coordination of physiological processes. Circadian misalignment, stemming from modern life style, draws increasing attention due to its tight association with the development of metabolic, cardiovascular, inflammatory and mental diseases as well as cancer. This review highlights recent findings emphasizing the role of the circadian system in the temporal orchestration of physiology, with a particular focus on implications of circadian misalignment in human pathologies.