Synapses are specialized intercellular junctions connecting pre- and postsynaptic neurons into functional neural circuits. Synaptic cell adhesion molecules (CAMs) constitute key players in synapse development that engage in homo- or heterophilic interactions across the synaptic cleft. Decades of research have identified numerous synaptic CAMs, mapped their trans- synaptic interactions, and determined their role in orchestrating synaptic connectivity. However, surprisingly little is known about the molecular mechanisms that translate trans -synaptic adhesion into the assembly of pre- and postsynaptic compartments. Here, we provide an overview of the intracellular signaling pathways that are engaged by synaptic CAMs and highlight outstanding issues to be addressed in future work.