The discovery that neurotransmitter identity is regulated by activity in the adult mammalian brain during a stress response raises questions about the extent and function of this plasticity. Specific synapses are associated with the release of a particular neurotransmitter or transmitters on the basis of evidence obtained under a single set of conditions. Transmitter switching endows the connectome with greater plasticity: Activity-dependent revision of signaling provides another dimension of flexibility to regulate normal behavior. Changes in transmitter identity are also positioned to contribute to diseases of the nervous system. Neurotransmitter imbalance has long been implicated in common neurological and psychiatric disorders, provoking interest in transmitter switching as a therapeutic tool for patients.