CD100 is a 150 kDa transmembrane protein that belongs to the semaphorin family. Many members of the semaphorin family are known to play crucial roles in axon guidance, acting as chemorepulsive factors during neuronal development. CD100 is the first member of the semaphorin family for which crucial roles in the immune system have been identified. Although plexin-B1 has been shown to be the receptor for CD100 in nonlymphoid tissues, CD72 functions as its receptor in lymphoid tissues. CD100 plays a nonredundant role in the immune response by a unique mechanism that involves switching off the negative signals mediated by CD72.