Paired associative stimulation (PAS) refers to a paradigm consisting of slow-rate repetitive low-frequency median nerve stimulation combined with transcranial magnetic stimulation (TMS) over the contralateral motor cortex. This protocol has been shown to induce plastic changes of excitability in the human motor cortex. Its principles of design were shaped after associative long-term potentiation (LTP) in experimental animals, a cellular mechanism likely to be relevant for learning and memory. PAS-induced changes of cortical excitability share a number of physiological properties with LTP. Of particular importance is the fact that the sign of PAS-induced changes of the size of amplitudes of the motor evoked potentials (MEPs) depends on the exact interval between the afferent and the magnetic pulse during the intervention. A number of observations suggest that PAS-induced excitability changes may have functional significance. PAS-induced plasticity may contribute to elucidating the pathogenesis of neurological disorders where neuroplasticity is thought to have a pathogenetic role. Finally, PAS-induced plasticity may itself have therapeutic potential.