Altered intracellular calcium levels are a consistent finding in studies of bipolar disorder, and recent studies point to the role of mitochondrial dysfunction, leading to the possibility that mitochondrial calcium dysregulation is involved in the pathophysiology of the disease. Although the mitochondrion is a key organelle for calcium accumulation, initial calcium signaling studies in bipolar disorder did not focus on the role of mitochondria. Later, neuroimaging and molecular genetic studies suggested the possibility that altered mitochondrial calcium regulation due to mitochondrial DNA (mtDNA) polymorphisms/mutations might be involved in the pathophysiology of bipolar disorder. Recent studies show that certain mtDNA polymorphisms alter mitochondrial calcium levels. Mutant mtDNA polymerase (Polg) transgenic mice carrying mtDNA mutations in forebrain cells show an increased calcium uptake rate in isolated mitochondria. This was found to be mediated by downregulation of cyclophilin D, a component of the mitochondrial permeability transition pore. In addition, agonist-stimulated calcium response is attenuated in hippocampal neurons of these transgenic mice. The finding that mtDNA polymorphisms and mutations affect mitochondrial calcium regulation supports the idea that mitochondrial calcium dysregulation may be involved in the pathophysiology of bipolar disorder. In this review, the history and recent findings of studies elucidating the role of mitochondrial calcium signaling in bipolar disorder are summarized.