Mitochondrial dysfunction is suggested to play a role in the pathophysiology of bipolar disorder based on the studies of neuroimaging, genetics, postmortem brain analyses, pharmacology, cellular and animal models, and biomarkers. Mitochondria have two major functions: the production of adenosine triphosphate (ATP) and regulation of calcium. Since intracellular calcium signaling is implicated by genetic studies of bipolar disorder, the role of mitochondria in regulating intracellular calcium signaling is especially important. The next step of the mitochondrial dysfunction hypothesis is to search for the neural circuit affected by mitochondrial dysfunction, identify relevant biomarkers, and develop drugs targeting mitochondria. This chapter discusses the history of the mitochondrial dysfunction hypothesis, the current situation, and future directions.