Calcium-signaling plays a central role in specification of the chemical transmitters neurons express, adjusting the numbers of cells that express excitatory and inhibitory transmitters as if to achieve homeostatic regulation of excitability. Here we review the extent to which this activity-dependent regulation is observed for a range of different transmitters. Strikingly the homeostatic paradigm is observed both for classical and for peptide transmitters and in mature as well as in embryonic nervous systems. Transmitter homeostasis adds another dimension to homeostatic regulation of function in the nervous system that includes regulation of levels of voltage-gated ion channels, densities of neurotransmitter receptors, and synapse numbers and strength. (c) 2005 Elsevier Ltd. All rights reserved.