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Semaphorins provide crucial attractive and repulsive cues involved in axon guidance. Several semaphorins have also been detected in cells of the immune system. Their influence on cell motility has been reported and is reminiscent of the biological function attributed to nervous system semaphorins. Receptors of the plexin and neuropilin family of proteins, also expressed by some immune cells, may be involved in semaphorin signaling in the immune system. However, semaphorins also affect the functioning of the immune system through receptors regulating lymphocyte activation. An important challenge in the future will be to determine whether, as in the nervous system, semaphorins help immune cells to establish connections with their appropriate targets.