In this paper, we show the importance of intracellular calcium (Ca2+) signaling systems in the pathophysiology of mood disorders based on our recent work. Patients with affective disorders appear to have an enhanced intracellular Ca2+ rise in response to serotonin. We have observed effects of antidepressant drugs on intracellular Ca2+ signaling in rat cultured neuronal cells and glioma cells, and found that acute application of several classes of antidepressant drugs inhibited intracellular Ca2+ signaling and Ca2+-related signaling. It is important to investigate the role of intracellular Ca2+ signaling system for an understanding of the pathophysiology of affective disorders.