The understanding of the mode of action of spinal cord stimulation (SCS) as treatment of neuropathic pain is still fragmentary. SCS evolved from the gate-control theory postulating a spinal modulation of noxious inflow, but there is little evidence that SCS influences nociceptive pain; pain relief in peripheral vascular disease and angina pectoris is presumably secondary to other SCS effects. In man, SCS may effectively abolish both continuous and evoked pain (tactile/thermal allodynia) whereas induced, acute nociceptive pain is unaffected. Recent SCS studies performed on rat models of mononeuropathy have demonstrated a preferential effect on A beta fiber mediated functions, and the hyperexcitability of wide-dynamic-range dorsal horn neurons was attenuated. These effects were coupled to increased release of GABA and reduced glutamate and aspartate release in the dorsal horn. Intrathecal administration of GABA, baclofen and adenosine enhanced the SCS effect on tactile allodynia even in previously non-responsive rats. Preliminary results indicate that gabapentin may have a similar effect. GABAergic and adenosine-related mechanisms conceivably represent only examples of a number of putative receptor systems involved in SCS. Clinical trials have been initiated exploring the possibility to improve the efficacy of SCS by concomitant pharmacotherapy.