The signals mediating synaptic differentiation are critical for our understanding of synapse formation and nervous system development. Recent progress highlights the roles of membrane-bound and soluble signaling pathways in this process. The postsynaptic adhesion molecules neuroligin-1, neuroligin-2, and SynCAM1 provide target-derived signals leading to the assembly of presynaptic terminals. In the reverse direction, neuroligins also relay signals into postsynaptic sites through interactions with their presynaptic partners, the beta-neurexins. This adhesion-based system helps to determine the neurotransmitter specificity of postsynaptic specializations. In addition, soluble molecules are released from target neurons and initiate presynaptic differentiation, as demonstrated for the fibroblast growth factor FGF-22. This Perspective summarizes new insights into early synaptic differentiation signals and discusses underlying principles.