Glutathione peroxidases (GPx, Fig. 1) belong to a widespread family of proteins that, over the years, have been discovered in almost all kingdoms of life.[1] They catalyze the reduction of H2O2 or organic hydroperoxides to water or corresponding alcohols, thus mitigating their toxicity.[2] The global reaction is ROOH+2GSH  GSSG+ROH+H2O, where GSH indicates glutathione. In the GPx family the active site SeCys or Cys is surrounded by highly conserved residues (Asn, Gln and Trp) forming the catalytic tetrad. One of the main open questions is about the specific role of either SeCys or Cys in the catalysis: it is not yet clear why selenium rather than sulphur has been chosen by nature selection given that a complex and energetically very expensive co-traslational insertion machinery for SeCys is needed. Fig. 1 GPx Fig. 2 Model catalytic site The basic catalytic scheme involves three main steps, i.e. (i) O-O bond cleavage and formation of selenenic/sulphenic acid Se/S-OH and ROH; (ii) formation of a seleno-sulfide (disulfide) intermediate and elimination of H2O; (iii) formation of the disulfide product and regeneration of the catalyst. We present a detailed investigation of different possible paths of the reduction of H2O2 catalyzed by Se-based as well as S-based GPxs with the aim of validating at quantum chemistry (DFT) level the experimental findings obtained by recent mass spectrometry and biochemistry methods (enzymatic kinetics); a core of seven aminoacids has been identified, which suitably represents the GPx core (Fig. 2). From our results a complex energy landscape emerges, where novel mechanistic paths are possible and novel perspectives on the intriguing behaviour of GPx can be outlined.