The article reviews the molecular architecture of the mammalian circadian clock, highlighting recent advances in understanding how this intrinsic 24-hour clock integrates with environmental and metabolic stimuli to regulate physiology and behavior. The core molecular clock is based on interlocked transcription/translation feedback loops involving four key proteins: CLOCK, BMAL1, PER, and CRY. These proteins regulate gene expression, controlling the timing of physiological processes such as DNA repair and glucose metabolism. The clock is organized into a hierarchical system with a 'master' clock in the suprachiasmatic nucleus (SCN) that synchronizes peripheral clocks in various tissues. Recent studies have revealed that transcriptional and post-transcriptional mechanisms work together to generate tissue-specific circadian rhythms, with local control of peripheral clocks being crucial for tissue-specific physiology. The article also discusses the role of chromatin remodeling and RNA polymerase II occupancy in regulating transcriptional output, as well as the importance of post-transcriptional and translational control in generating circadian rhythms. Understanding these mechanisms may provide avenues for developing temporally directed therapeutics to improve health and prevent diseases.The article reviews the molecular architecture of the mammalian circadian clock, highlighting recent advances in understanding how this intrinsic 24-hour clock integrates with environmental and metabolic stimuli to regulate physiology and behavior. The core molecular clock is based on interlocked transcription/translation feedback loops involving four key proteins: CLOCK, BMAL1, PER, and CRY. These proteins regulate gene expression, controlling the timing of physiological processes such as DNA repair and glucose metabolism. The clock is organized into a hierarchical system with a 'master' clock in the suprachiasmatic nucleus (SCN) that synchronizes peripheral clocks in various tissues. Recent studies have revealed that transcriptional and post-transcriptional mechanisms work together to generate tissue-specific circadian rhythms, with local control of peripheral clocks being crucial for tissue-specific physiology. The article also discusses the role of chromatin remodeling and RNA polymerase II occupancy in regulating transcriptional output, as well as the importance of post-transcriptional and translational control in generating circadian rhythms. Understanding these mechanisms may provide avenues for developing temporally directed therapeutics to improve health and prevent diseases.