Redox (reduction-oxidation) reactions control many important biological processes in all organisms, both prokaryotes and eukaryotes. This reaction is usually accomplished by canonical disulfide-based pathways involving a donor enzyme that reduces the oxidized cysteine residues of a target protein resulting in the cleavage of its disulfide bonds. Focusing on the human vitamin K epoxide reductase (hVKORC1) as a target and on the four redoxins (PDI, ERp18, Tmx1 and Tmx4) as the most probable reducers of VKORC1, a comparative in silico analysis is provided that concentrates on the similarity and divergence of redoxins in their sequence, secondary and tertiary structure, dynamics, intra-protein interactions and composition of the surface exposed to the target. Similarly, the hVKORC1 is analysed in the native state, where two pairs of cysteine residues are covalently linked forming two disulphide bridges, as a target for Trx-fold proteins. Such analysis is used to derive the putative recognition/binding sites on each isolated protein, and the Protein Disulfide Isomerase (PDI) is suggested as the most probable hVKORC1 partner. By probing the alternative orientation of PDI with respect to hVKORC1, the functionally related non-covalent complex formed by hVKORC1 and PDI is found, which is proposed as a first precursor to probe the thiol-disulfide exchange reactions between PDI and hVKORC1.