The efficacy of many of pain-relieving drugs is based on mechanisms by which the drugs interfere with the body’s natural pain-mediating pathways. By contrast, although it is less popular, other drugs including opioids exert more powerful analgesic actions by augmenting endogenous inhibitory neural circuits for pain mediation. Recently, a novel endogenous pain-inhibitory principle was suggested and is now attracting both scientific and clinical attentions. The central players for the actions are particular body lipids: resolvins. Although research is in the preclinical phase, multiple hypotheses have actively been matured regarding the potency and molecular and neural processes of the analgesic effects of these substances. Consistently, accumulating experimental evidence has been demonstrating that treatment with these lipid substances is strongly effective at controlling diverse types of pain. Treatment of resolvins does not appear to disturb the body homeostasis as severely as many other therapeutic agents that interrupt the body’s natural signaling flow, which enables us to predict their fewer adverse effects. This paper serves as a review of currently documented painkilling actions of resolvins, summarizes the potential cellular and receptor-mediated mechanisms to date, and discusses the many clinical uses for these therapeutic lipids that have not yet been tested. Future scientific efforts will more concentrate to unveil such aspects of the substances and to construct clear proofs of concept for pain relief.