Extensive neuronal cell death during development is believed to be due to a limiting supply of neurotrophic factors.In vitrostudies suggest that axon guidance molecules directly regulate neuronal survival, raising the possibility that they play a direct role in neuronal cell deathin vivo. However, guidance errors may also influence survival indirectly due to loss of target-derived neurotrophic support. The role of guidance molecules in neuronal deathin vivohas thus been difficult to decipher. Semaphorin3A, a repulsive guidance cue for sensory neurons, can induce sensory neuron deathin vitro. Null mice studies of the Semaphorin3A coreceptors showed that guidance activity is mediated by PlexinA4, but PlexinA3 partially compensates in PlexinA4−/−mice. Here we demonstrate that both Plexins contribute to Sema3A-induced cell deathin vitro, albeit in a different hierarchy. PlexinA3 is absolutely required, while PlexinA4 makes a smaller contribution to cell death. We found that PlexinA3−/−mice, which, unlike PlexinA4−/−mice, do not exhibit sensory axon patterning defects, show reduced neuronal apoptosis and an increased number of DRG neurons. Semaphorin3A involvement in neuronal deathin vivowas demonstrated by a sensitization experiment using the proapoptotic effectorBax. Our results identify Plexins as mediators of Semaphorin-induced cell deathin vitro, and provide the first evidence implicating Semaphorin/Plexin signaling in neuronal survival independent of its role in axon guidance. The results also support the idea that naturally occurring neuronal cell death reflects not only competition for target-derived trophic factors, but also the action of proapoptotic signaling via a Semaphorin/Plexin pathway.