Abnormal activation of the immune response system has been suggested to play a role in the pathophysiology of bipolar disorder (BD). Increased levels of inflammatory mediators such as cytokines and chemokines, but also alterations in immune cell population and neurotrophins, have been reported. This chapter summarizes the role of the immune system in BD, the interaction between the immune system and the core players in the pathophysiology of the disorder such as the biological clock and the serotoninergic and dopaminergic neurotransmission, the possible mechanisms underlying the activation of the immune response system, and the main biomarkers emerged from the literature in the last decades. Further, an overview of anti-inflammatory and immunomodulatory treatments is given.