l-methionine (l-Met) is the only sulphur-containing proteinogenic amino acid together with cysteine. Its importance is highlighted by it being the initiator amino acid for protein synthesis in all known living organisms. l-Met, free or inserted into proteins, is sensitive to oxidation of its sulfide moiety, with formation of l-Met sulfoxide. The sulfoxide could not be inserted into proteins, and the oxidation of l-Met in proteins often leads to the loss of biological activity of the affected molecule. Key discoveries revealed the existence, in rats, of a metabolic pathway for the reduction of free l-Met sulfoxide and, later, in Escherichia coli, of the enzymatic reduction of l-Met sulfoxide inserted in proteins. Upon oxidation, the sulphur atom becomes a new stereogenic center, and two stable diastereoisomers of l-Met sulfoxide exist. A fundamental discovery revealed the existence of two unrelated families of enzymes, MsrA and MsrB, whose members display opposite stereospecificity of reduction for the two sulfoxides. The importance of Msrs is additionally emphasized by the discovery that one of the only 25 selenoproteins expressed in humans is a Msr. The milestones on the road that led to the discovery and characterization of this group of antioxidant enzymes are recounted in this review.