The multigene family of GPxs encodes for tetrameric and monomeric enzymes both containing either a selenocysteine (Sec) or cysteine (Cys) residue at the catalytic site. Monomeric GPxs carry deletions of the subunit interfaces. The Sec containing homologues are found in vertebrates, and, with a scattered presence, in lower organisms. These SecGPxs are either tetrameric or monomeric, as the mammalian GPx-1 and 4 respectively, and undergo a peroxidatic cycle where the selenenic acid derivative of Sec (SeOH), formed upon reaction with the peroxide, is reduced back at a fast rate by glutathione (GSH). On the other hand, terrestrial plants, insects, bacteria, fungi, do not encode for any SecGPxs, but for CysGPxs only. By analyzing more than 450 GPx sequences, we have found that the majority of these both carry a non-aligned ‘second’ Cys residue in the fourth helix and have a monomeric nature, being, in the latter respect, GPx-4 homologues. In these CysGPxs, the oxidized intermediate of the catalytic cycle is different from SecGPxs, being accounted for by a disulfide between the peroxidatic Cys and the ‘second’ Cys, thus acting as a ‘resolving’ Cys, as typically in peroxiredoxins. Conformation analysis suggests that the absence of tetrameric structure allows the loop flexibility required for the disulfide formation. Taking as a paradigm the Drosophila CysGPx, we have shown that the above features largely favor the reaction with Thioredoxin (Trx) over GSH. Thus, the majority of the CysGPxs sequences deposited in the data banks, in functional terms, must be referred to as Trx peroxidases. On the other hand, the functional role of the quantitatively minor tetrameric or monomeric CysGPxs sequences, lacking the resolving Cys, which, in vertebrates, are coexisting together with the SecGPxs, remains unresolved. GPxs are not redundant proteins. In yeast one of the above CysGPxs, GPX3, has been shown to be involved in the peroxide-dependent activation of the trascription factor Yap-1 (Toledano et al. TIBS 29, 351, (2004). While in mammals, GPx-1 appears the unique, real, glutathione peroxidase out of the five SecGPxs, the others might have different functions. In particular, GPx-4 is involved in the oxidation of protein thiol motifs taking place during sperm maturation.