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Semaphorins constitute one of the largest families of repulsive and attractive growth cone guidance proteins. They affect the growth cone’s actin cytoskeleton through interactions with receptor complexes composed of ligand-binding, signal-transducing, and modulatory subunits. Our understanding of the intracellular signal transduction machinery linking semaphorins to actin dynamics is limited; however, recent advances provide a more comprehensive view of the molecular basis of neuronal semaphorin signaling.