Different physiological as well as behavioral processes such as sleep-wake cycles, thermoregulation, hormonal secretions, blood pressure and metabolism exhibits 24-hour rhythmicity which is generated through a molecular machinery involving transcriptional-translational feedback loop in the suprachiasmatic nucleus (SCN) of hypothalamus and many peripheral tissues. Mammalian circadian system contains a set of core CLOCK genes that encode proteins such as CLOCK (circadian locomotor output kaput), BMAL1 (brain and muscle ARNLT1), PER (period), CRY (cryptochrome), REV-ERB alpha, and ROR alpha. CLOCK was the first gene identified in its family and CLOCK protein binds DNA for activating transcription after dimerization with BMAL1 by driving the rhythmic transcription of other CLOCK and circadian clock-controlled genes through an E-box (5'-CACGTG-3'). It activates transcription of PER1/PER2 which is inhibited in a feedback loop by PER and CRY proteins. With its intrinsic histone acetyltransferase activity, CLOCK acetylates histones H3, histone H4, and ARNTL (non-histone substrate), and has also been shown to plays a role in DNA damage response/DDR signaling during the S phase of cell cycle. Because this endogenous timekeeper interacts with countless biological systems, CLOCK dysfunctions may lead to the pathogenesis of several diseases including sleep disorders, metabolic syndrome, cardiovascular and inflammatory disease, and cancer.