The mammalian circadian clock is a molecular system that coordinates physiology and behavior with the 24-hour solar day to maintain temporal homeostasis. It is based on interlocked transcription/translation feedback loops that integrate diverse environmental and metabolic signals to generate internal 24-hour timing. Recent advances highlight the core molecular clock and its use of diverse transcriptional and post-transcriptional mechanisms to regulate mammalian physiology. Understanding these mechanisms may lead to temporally-directed therapeutics for health and disease prevention. The circadian clock is genetically encoded in nearly every cell, generating an internal 24-hour rhythm in the absence of external cues. A master clock in the suprachiasmatic nucleus (SCN) of the hypothalamus synchronizes internal timing with the external solar day, passing this information to peripheral clocks via endocrine and systemic cues. Peripheral clocks share the same molecular architecture but differ in intercellular coupling. The SCN forms a highly unified circadian network resistant to phase perturbations, while peripheral clocks are susceptible to adjustment from the SCN via hormones and metabolic cues. The core circadian clock is driven by two interlocking transcription/translation feedback loops (TTFLs). The first involves four clock proteins: two activators (CLOCK and BMAL1) and two repressors (PER and CRY), along with kinases and phosphatases that regulate their localization and stability. The second TTFL is driven by retinoid-related orphan receptors (RORa, b, c) and repression by REV-ERBα/REVERBβ. These loops drive rhythmic changes in Bmal1 transcription and introduce a delay in Cry1 mRNA expression, which is critical for proper circadian timing. Circadian regulation of physiology is locally controlled, with peripheral clocks regulating tissue-specific expression patterns. Transcriptional control of circadian output is primarily at the transcriptional level, but post-transcriptional and translational regulation also play important roles. The heterodimeric CLOCK:BMAL1 complex is the essential positive regulator of circadian transcription, binding to DNA sites and recruiting repressor complexes to inhibit transcription. The interplay of transcriptional and post-transcriptional regulatory mechanisms determines circadian output, with recent studies revealing that only ~22-30% of cycling mRNAs have robust circadian rhythms of transcription. The circadian clock links daily epigenetic changes and RNAPII occupancy to transcriptional activation. Temporal control of transcriptional output is robustly regulated by the clock, with RNAPII recruitment and promoter escape playing key roles. The clock also links daily epigenetic changes and RNAPII occupancy to transcriptional activation, with chromatin remodeling playing an important role in priming the epigenetic landscape for circadian regulation. Post-transcriptional and translational control of circadian output is also important, with proteins such as FUS, CIRP, and Nocturnin playing rolesThe mammalian circadian clock is a molecular system that coordinates physiology and behavior with the 24-hour solar day to maintain temporal homeostasis. It is based on interlocked transcription/translation feedback loops that integrate diverse environmental and metabolic signals to generate internal 24-hour timing. Recent advances highlight the core molecular clock and its use of diverse transcriptional and post-transcriptional mechanisms to regulate mammalian physiology. Understanding these mechanisms may lead to temporally-directed therapeutics for health and disease prevention. The circadian clock is genetically encoded in nearly every cell, generating an internal 24-hour rhythm in the absence of external cues. A master clock in the suprachiasmatic nucleus (SCN) of the hypothalamus synchronizes internal timing with the external solar day, passing this information to peripheral clocks via endocrine and systemic cues. Peripheral clocks share the same molecular architecture but differ in intercellular coupling. The SCN forms a highly unified circadian network resistant to phase perturbations, while peripheral clocks are susceptible to adjustment from the SCN via hormones and metabolic cues. The core circadian clock is driven by two interlocking transcription/translation feedback loops (TTFLs). The first involves four clock proteins: two activators (CLOCK and BMAL1) and two repressors (PER and CRY), along with kinases and phosphatases that regulate their localization and stability. The second TTFL is driven by retinoid-related orphan receptors (RORa, b, c) and repression by REV-ERBα/REVERBβ. These loops drive rhythmic changes in Bmal1 transcription and introduce a delay in Cry1 mRNA expression, which is critical for proper circadian timing. Circadian regulation of physiology is locally controlled, with peripheral clocks regulating tissue-specific expression patterns. Transcriptional control of circadian output is primarily at the transcriptional level, but post-transcriptional and translational regulation also play important roles. The heterodimeric CLOCK:BMAL1 complex is the essential positive regulator of circadian transcription, binding to DNA sites and recruiting repressor complexes to inhibit transcription. The interplay of transcriptional and post-transcriptional regulatory mechanisms determines circadian output, with recent studies revealing that only ~22-30% of cycling mRNAs have robust circadian rhythms of transcription. The circadian clock links daily epigenetic changes and RNAPII occupancy to transcriptional activation. Temporal control of transcriptional output is robustly regulated by the clock, with RNAPII recruitment and promoter escape playing key roles. The clock also links daily epigenetic changes and RNAPII occupancy to transcriptional activation, with chromatin remodeling playing an important role in priming the epigenetic landscape for circadian regulation. Post-transcriptional and translational control of circadian output is also important, with proteins such as FUS, CIRP, and Nocturnin playing roles