Fragile X syndrome (FXS), the most common heritable form of mental retardation, is characterized by synaptic dysfunction. Synaptic transmission depends critically on presynaptic calcium entry via voltage-gated calcium (Ca(V)) channels. Here we show that the functional expression of neuronal N-type Ca(V) channels (Ca(V)2.2) is regulated by fragile X mental retardation protein (FMRP). We find that FMRP knockdown in dorsal root ganglion neurons increases Ca(V) channel density in somata and in presynaptic terminals. We then show that FMRP controls Ca(V)2.2 surface expression by targeting the channels to the proteasome for degradation. The interaction between FMRP and Ca(V)2.2 occurs between the carboxy-terminal domain of FMRP and domains of Ca(V)2.2 known to interact with the neurotransmitter release machinery. Finally, we show that FMRP controls synaptic exocytosis via Ca(V)2.2 channels. Our data indicate that FMRP is a potent regulator of presynaptic activity, and its loss is likely to contribute to synaptic dysfunction in FXS.