Chronic pain is frequently associated with profound alterations of neuronal systems involved in pain processing and should be considered as an actual disease state of the nervous system. It should not only be relieved, but must really be treated in suffering patients. However, some forms of chronic pain, in particular those of neuropathic origin, are most often not satisfactorily managed with currently available pharmacological agents, some of which, in addition, may be poorly tolerated by some patients. In this context, gene-based approaches may contribute to the search for a better management of chronic pain. The question then arises regarding the most appropriate level for such an intervention using gene-transfer techniques. The first experimental protocols attempted the transfer of opioid precursor genes and their overexpression mainly at the spinal level. They demonstrated the feasibility and the real interest of these approaches by showing that local overproduction of opioid peptides induced antinociceptive effects in animal models of persistent pain, of inflammatory-, neuropathic- and even cancerous origin. Although really tempting data were obtained using gene-based techniques in experimental inflammatory diseases, the possible clinical interest of these approaches in chronic pain has still to be established. Nevertheless, targeting some proinflammatory cytokines, involved not only in inflammation but also in the induction and probably the perpetuation of pain, raises the possibility to block the “development” of chronic pain rather that to “simply” relieve established ongoing pain. Future gene-based protocols will certainly target some of the recently identified molecules involved in pain transduction mechanisms, sensory nerve sensitization or pain perpetuation, and evaluate their potential interest to ideally abolish or, at least, reduce chronic pain.