Serotonin (5-HT), a well-known neurotransmitter in the brain, also plays an important role in peripheral tissues, including the immune system. There is a growing body of evidence suggesting that many different types of immune cells express the machinery to generate, store, respond to and/or transport serotonin, including T cells, macrophages, mast cells, dendritic cells and platelets. In addition, there is emerging evidence of a possible connection between T cells, serotonin and mood disorders. How 5-HT interacts with the peripheral immune system and if this signaling is associated with behavioral phenotypes found in mood disorders like major depressive disorder (MDD) is not well understood. In this review, we summarize the existing literature on what is known about the link between 5-HT and the immune system and the effects of 5-HT signaling on different cells of the peripheral immune system, with a particular focus on T cells. In addition, we review the current evidence that peripheral immune system alterations and CNS function may be interrelated and the possible implications of these findings for drug discovery.