The release of transmitters through vesicle exocytosis from nerve terminals is not constant but is subject to modulation by various mechanisms, including prior activity at the synapse and the presence of neurotransmitters or neuromodulators in the synapse. Instantaneous responses of postsynaptic cells to released transmitters are mediated by ionotropic receptors. In contrast to metabotropic receptors, ionotropic receptors mediate the actions of agonists in a transient manner within milliseconds to seconds. Nevertheless, transmitters can control vesicle exocytosis not only via slowly acting metabotropic, but also via fast acting ionotropic receptors located at the presynaptic nerve terminals. In fact, members of the following subfamilies of ionotropic receptors have been found to control transmitter release: ATP P2X, nicotinic acetylcholine, GABA(A), ionotropic glutamate, glycine, 5-HT(3), andvanilloid receptors. As these receptors display greatly diverging structural and functional features, a variety of different mechanisms are involved in the regulation of transmitter release via presynaptic ionotropic receptors. This text gives an overview of presynaptic ionotropic receptors and briefly summarizes the events involved in transmitter release to finally delineate the most important signaling mechanisms that mediate the effects of presynaptic ionotropic receptor activation. Finally, a few examples are presented to exemplify the physiological and pharmacological relevance of presynaptic ionotropic receptors.