Nearly all patients with bipolar disorder have severely disrupted circadian rhythms. Treatment with mood stabilizers can restore these daily rhythms, and this is correlated with patient recovery. However, it is still uncertain whether clock abnormalities are the cause of bipolar disorder or if these rhythm disruptions are secondary to alterations in other circuits. Furthermore, the mechanism by which the circadian clock might influence mood is still unclear. With cloning and characterization of the circadian genes and recent advances in molecular biology, we are starting to understand this strong association between circadian rhythms and bipolar disorder. Recent human genetic and mouse behavioral studies indicate that the Clock gene is particularly relevant in the mood disruptions associated with this disorder. Furthermore, it appears that Clock expression outside of the central pacemaker of the suprachiasmatic nucleus (SCN) is involved in mood regulation. In this chapter, the evidence linking circadian rhythms, the Clock gene, and bipolar disorder is discussed, along with the possible biology that underlies this connection.