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Understanding percepts, engrams and actions requires methods for selectively modulating synaptic communication between specific subsets of interconnected cells. Here, we develop an approach to control synaptically connected elements using bioluminescent light: Luciferase-generated light, originating from a presynaptic axon terminal, modulates an opsin in its postsynaptic target. Vesicular-localized luciferase is released into the synaptic cleft in response to presynaptic activity, creating a real-time Optical Synapse. Light production is under experimenter-control by introduction of the small molecule luciferin. Signal transmission across this optical synapse is temporally defined by the presence of both the luciferin and presynaptic activity. We validate synaptic Interluminescence by multi-electrode recording in cultured neurons and in mice in vivo. Interluminescence represents a powerful approach to achieve synapse-specific and activity-dependent circuit control in vivo., Prakash et al. develop an approach to control synaptically connected elements using bioluminescent light, in which Luciferase-generated light, originating from a presynaptic axon terminal, modulates an opsin in its postsynaptic target to form an ‘optical synapse’. They validate their optical synapses in cultured neurons and in mice in vivo and show that they provide an approach to achieve synapse-specific and activity-dependent circuit control in vivo.