Semaphorins were identified originally as guidance cues for developing axons. However, it is becoming clear that several semaphorins are crucially involved in the immune system. For instance, Sema4D (CD100) enhances activation of B cells and dendritic cells, and Sema4A is involved in T cell priming and Th1/Th2 regulation. In addition, recent cumulative evidence reveals their importance in immunological homeostasis. We here focus on our current understanding of the roles of semaphorins in autoimmunity.