To characterize endogenous molecules regulating nociception, various groups have focused on dehydroepiandrosterone (DHEA). Indeed, DHEA modulates NMDA and P2X receptors which control neurobiological activities including nociception. Thus, various results were published on DHEA ability to regulate nociception but the data were interpreted separately. To provide an overview, we analyzed here the current knowledge on DHEA regulatory action on the spinal cord (SC) which is pivotal for nociception. DHEA endogenously synthesized in the SC appears as a key factor regulating nociception. However, DHEA effects on nociceptive mechanisms are complex. Acute DHEA treatment exerts a biphasic effect on nociception (a rapid pro-nociceptive action and a delayed anti-nociceptive effect). Chronic DHEA treatment increased basal nociceptive thresholds in neuropathic and control rats, suggesting that androgenic metabolites of DHEA exerted analgesic effects while DHEA itself caused a rapid pro-nociceptive action. To get more insights into DHEA effects on nociception, we provided a hypothetical scheme recapitulating cellular mechanisms of action of DHEA in the control of nociception. Perspective is opened for the development of DHEA-based strategies against pathological pain.