e., Per1 to Per3 and Cry1 and Cry2) as well as a host of other clock-controlled genes. When PER and CRY proteins accumulate in the cytosol, they heterodimerize and translocate to the nucleus where they act as transcriptional repressors to terminate CLOCK-BMAL1�Cmediated transcription, thus ending the molecular circadian cycle (van der Horst et al. 1999) (see figure 3). The cycle is further regulated by additional proteins, including the enzyme sirtuin 1 (SIRT1), a histone deacetylase that modifies circadian proteins or DNA by removing acetyl groups to alter gene expression. SIRT1 is sensitive to levels of the coenzyme nicotinomide adenine dinucleotide (NAD+), making NAD availability a potential regulator of the molecular circadian clock (Grimaldi et al. 2009). The details of this oscillating cycle are found elsewhere (Reppert and Weaver 2002). Figure 3 The molecular circadian clock. Transcription of the clock-controlled genes, including Per and Cry is initiated by the heterodimerization and binding of BMAL1 and CLOCK (the positive limb of the molecular circadian clock). Once sufficient amounts of PER … Demonstrating the importance of the molecular circadian clock, mutations of the core circadian clock components can have a devastating effect on the function of the circadian clock. This is true for both Bmal1 (Bunger et al. 2000) and Clock (Oishi et al. 2006). Likewise, molecular perturbation of the circadian clock (i.e., altering the Clock, Bmal1, Per1, Per2, Cry1, or Cry2 expression via genetic manipulations including deleting or mutating the gene of interest to affect the levels of functional protein produced) disrupts normal circadian behavioral rhythms (Antoch et al. 1997; Bunger et al. 2000; van der Horst et al. 1999; Zheng et al. 2001). This article will discuss the influence of alcohol on circadian rhythms and how circadian-rhythm disruption affects immune function and metabolism, significant factors for alcohol-associated poor health outcomes. It also will discuss potential epigenetic mechanisms by which circadian disruption and alcohol may establish long-term changes in gene expression, resulting in adverse health outcomes. Alcohol and Circadian Rhythmicity Circadian organization and stable circadian rhythms are vital for optimal health as numerous diseases are associated with circadian-rhythm disruption. Environmental factors such as shift work or jet lag are obvious disrupters of circadian rhythmicity. However, other environmental factors, such as alcohol consumption and the timing of food intake, can profoundly disrupt and disorganize circadian rhythmicity, which can be observed on behavioral, cellular, and molecular levels. Alcohol Disrupts Behavioral and Biological Circadian Rhythms Alcohol has a dramatic effect on circadian rhythms. These circadian abnormalities include disrupted sleep/wake cycles in humans (Brower 2001; Imatoh et al.