Quinone reductase 2 has been discovered in 1961 and rediscovered in 1997. Because of its sequence homology with quinone reductase 1, it has been suspected to detoxify quinones. Ten years later, evidences begin to point to a versatile role of this enzyme. Indeed, QR2 is strongly suspected to be the molecular target of anti-malarian drugs such as chloroquin or paraquine, and of red wine-derived resveratrol that might be responsible for the so-called French paradox. It also is identical to the melatonin binding site MT3, and might therefore be a rationale explanation for the antioxidant role of melatonin. Finally QR2 might be implicated in the toxicity, in vivo, of quinones such as menadione. The present commentary attempts to summarize this information and discusses a series of hypotheses.