Microtubules are well known to play a key role in the trafficking of neurotransmitters to the synapse. However, less attention has been paid to their role as downstream effectors of neurotransmitter signaling in the target neuron. Here, we show that neurotransmitter-based signaling to the microtubule cytoskeleton regulates downstream microtubule function through several mechanisms. These include tubulin posttranslational modification, binding of microtubule-associated proteins, release of microtubule-interacting second messenger molecules, and regulation of tubulin expression levels. We review the evidence for neurotransmitter regulation of the microtubule cytoskeleton, focusing on the neurotransmitters serotonin, melatonin, dopamine, glutamate, glycine, and acetylcholine. Some evidence suggests that microtubules may even play a more direct role in propagating action potentials through conductance of electric current. In turn, there is evidence for the regulation of neurotransmission by the microtubule cytoskeleton. Synapse, 2010. © 2010 Wiley-Liss, Inc.