Semaphorins were originally discovered in the nervous system, and have been implicated in repulsive axon guidance during the development of nervous system. Semaphorins are also implicated in tumor progression, by affecting adhesion, migration of malignant cells and angiogenesis, and are involved in normal cardiovascular development. Recently, several semaphorins and their receptors are expressed in a variety of lymphoid and myeloid cells, and affect immune cell functions, including cell proliferation, differentiation, chemotaxis, and cytokine production. This review focuses on recent work on the functions of semaphorins in the immune system and autoimmune diseases.