The analgesic efficacy of cortical stimulation on refractory neuropathic pain has been established. Although it offers pain relief to 45-75% of the patients, this technique remains under evaluation and the definitive protocol for its application has not been established yet. The mechanisms underlying the analgesic efficacy of cortical stimulation are still largely unknown. Successive technical adaptations have been proposed and tried in order to reduce the number of non-responding patients. In this chapter, we summarize the limited amount of crucial information that has been acquired so far on pain processing in the central nervous system, on the functional pathophysiology of neuropathic pain and on the mechanisms underlying the efficacy of cortical stimulation. We also discuss key issues that could help to increase the success rate and enhance the future prospects of the technique.