Information transfer between nerve cells (neurons) forms the basis of behavior, emotion, and survival. Signal transduction from one neuron to another occurs at synapses, and relies on both electrical and chemical signal propagation. At chemical synapses, incoming electrical action potentials trigger the release of chemical neurotransmitters that are sensed by the connected cell and here reconverted to an electrical signal. The presynaptic conversion of an electrical to a chemical signal is an energy demanding, highly regulated process that relies on a complex, evolutionarily conserved molecular machinery. Here, we review the biophysical characteristics of this process, the current knowledge of the molecules operating in this reaction and genetic specializations that may have evolved to shape inter-neuronal signaling