Cholinesterase activity can be found in all kingdoms of living organism, yet cholinesterases involved in cholinergic transmission appeared only recently in the animal phylum [1]. The closest proteins homologous to the cholinesterases are the neuroligins. These proteins with an altered catalytic triad and no identified hydrolytic activity have well-identified cell adhesion properties. Comparing evolution of the cholinesterases and neuroligins with other proteins involved in synapse functioning may shed light on the common or divergent developmental regulation events involved into the setting and maintenance of cholinergic transmission versus the balance between inhibitory and excitatory synapses. This comparison and its implications will be presented.