A key challenge in neurobiology is understanding how synaptic organization establishes circuit function underlying cognition and behavior. Reconstructing brain circuits with synaptic resolution (“connectomics”) provides structural blueprints that help focus hypotheses about neuronal physiology and computation. Importantly, connectomes are not fixed, but instead undergo significant plasticity guided by molecular/genetic programs and sensory/environmental experience. To address a gap in our current understanding of mechanisms regulating connectome dynamics, we propose a new approach—molecular connectomics—combining the strengths of advanced transcriptomic, proteomic, and high-resolution imaging methodologies to investigate circuit plasticity across multiple biological scales (RNAs --> proteins --> subcellular compartments --> individual neurons --> multi-neuronal microcircuit ensembles). Using our platform, we will map molecular and structural plasticity within visual connectomes essential for circadian physiology/behavior, learning, and mood in the mammalian brain.