Animals exhibit a stunning array of natural behaviors, many of which are innate and controlled by intricate neural circuits genetically specified. In the fruit fly, connectomics work has revealed precise patterns of neuronal connectivity and their computational potential. However, we lack a molecular understanding of how such circuit connectivity is established with synaptic specificity, in part because it remains challenging to define the molecular landscape and interactions at subcellular resolution in intact tissue. Taking advantage of the well-defined and accessible Drosophila motion vision circuit, here we present an integrative approach combining cell surface proteomics with data derived from single-cell RNA sequencing (scRNAseq) and electron microscopy connectomics to reveal the molecular logic of synapse-specific interactions. We defined the cell surface proteome of key elements in the direction-selective circuitry of the fly brain, T4 and T5 cells, showing a high enrichment of cell adhesion molecules (CAMs). Interestingly, for many of these CAMs no mRNA expression was evident in T4 and T5 neurons from published scRNAseq datasets, suggesting that these CAMs are expressed by their synaptic partners. To explore how these protein repertoires provide T4 and T5 with their particular connectivity patterns, we defined synapse-specific protein-protein interactions using interactomic analysis and connectomic data. We are currently validating these candidate interactions through endogenous tagging of CAMs and high-throughput behavioral screens. Taken together, our integrative framework promises to reveal the molecular logic behind the formation and maintenance of synapse-specific connections.