Neurotransmitters are released by synaptic vesicle fusion at the active zone^,. The active zone of a synapse mediates Ca²⁺-triggered neurotransmitter release, and integrates presynaptic signals in regulating this release. Much is known about the structure of active zones and synaptic vesicles, but the functional relation between their components is poorly understood. Here we show that RIM1α, an active zone protein that was identified as a putative effector for the synaptic vesicle protein Rab3A^,, interacts with several active zone molecules, including Munc13-1 (ref. ) and α-liprins^,, to form a protein scaffold in the presynaptic nerve terminal. Abolishing the expression of RIM1α in mice shows that RIM1α is essential for maintaining normal probability of neurotransmitter release, and for regulating release during short-term synaptic plasticity. These data indicate that RIM1α has a central function in integrating active zone proteins and synaptic vesicles into a molecular scaffold that controls neurotransmitter release.