Transcranial Magnetic Stimulation (TMS) has transformed the approach to neuropsychiatric illness although many limitations remain. Without a mechanistic understanding of how TMS produces lasting therapeutic changes in the brain, advances will be serendipitous and TMS will only reach a fraction of its potential. There are unlimited combinations of parameters possible in TMS including stimulation intensity, frequency, pulse width, time on and off, patterns, and anatomic location. Moreover, the way each of these parameters affect the brain will change based on brain location, regional cell types, circuits and activity patterns specific to each disorder, and brain state will all determine outcome. It is therefore essential to establish the basic mechanism of TMS effects, so that the explosion of clinically-orientated, hypothesis-driven research will have a mechanistic rationale. Building on the extensive animal work in synaptic plasticity, I will bridge the basic neurobiological mechanisms of learning and cognition learned in my dissertation with the translational work of TMS I have learned during residency to address the major gap in TMS research: how does it produce lasting therapeutic changes in the brain? A mechanistic approach to this question remains essentially untested. I hypothesize that excitatory TMS (including high-frequency repetitive (r)TMS and intermittent theta-burst stimulation (TBS)) induces long-term potentiation (LTP), and inhibitory TMS (including low-frequency rTMS and continuous TBS) induces long-term depression (LTD). Both of these processes depend on neuronal and NMDA receptor activity, and both are under the influence of inhibitory gamma-aminobutryric acid (GABA) innervation. I propose a series of experiments in healthy human subjects combining pharmacologic manipulation of the LTP and LTD cascades with TMS treatment protocols to the motor cortex. Electrophysiologic approaches assessing motor evoked potentials (MEPs) with electromyography (EMG) will allow further elucidation of the contribution of glutamatergic versus GABAergic inputs, and will directly impact stimulation strategies. A mechanistic understanding of TMS-induced changes to the brain could unleash its full therapeutic potential, and thereby, transform the treatment of brain disorders.