The circadian clocks are vital to many organisms for their survival and adaption to the surrounding environment. More and more people are interested in the circadian clock and related researches. One of the key characteristics of this endogenous clock is its periodicity. Mechanisms underlying the mammalian circadian rhythms with ~24 h periodicity involve interlocked transcriptional and translational feedback loops. The circadian clock system in mammals consists of hierarchical structures, with the suprachiasmatic nucleus (SCN) as the central pacemaker and peripheral oscillators in other organs. In spite of the central and peripheral oscillators, the molecular mechanisms are the same within the SCN and peripheral organs. In the past decades, major achievements are accomplished by using forward and reverse genetics, as well as epigenetic approaches. In this review, we recapitulate the history of how clock-related genes were identified, and summarize the main achievements in genetics and epigenetics to understand the molecular underpinnings. We hope it can offer basic knowledge for further researches, a reference for experimental designs aiming to adjust organisms’ homeostasis by modulating the clock, and provide a foundation to build interdisciplinary research networks.