In the past decades, selective serotonin reuptake inhibitors (SSRIs) have been shown to exert several immunological effects, such as reduced lymphocyte proliferation, alteration of cytokine secretion and induction of apoptosis. Based on these effects, SSRIs were proposed as drugs for the treatment of autoimmune pathologies and graft-versus-host disease. This review summarizes preclinical and clinical evidence supporting a role for SSRIs in autoimmune diseases and graft-versus-host disease, and discusses what is known about the mechanism underlying these effects.