Spinal cord stimulation emerged as a spin-off from the classical gate-control theory, which, however, does not suffice to explain its clinical effects. Whether or not nociceptive forms of pain may be attenuated remains a controversial issue. Previous experimental studies aiming at elucidating the underlying mechanisms were performed on intact, anesthetized animals and were therefore of limited clinical relevance. Not until recent years have some data on the mode of action accumulated providing evidence that gamma-aminobutyric acid (GABA) ergic as well as adenosine-related mechanisms are involved in the pain amelioration. It appears that the effects are exerted mostly via segmental spinal levels, but recent evidence suggests that a supraspinal loop may also be of importance; this issue remains to be resolved. It should be emphasized that most experimental data pertaining to the mode of action are derived from so-called animal models of neuropathic pain. However, caution must be exercised in the translation of such data from bench to bedside, because some behavioral signs interpreted as "pain" in such models may be misleading. We still need animal studies to generate basic data but these findings should also be confirmed in humans.