Diverse forms of mercury (Hg) have various effects on animals and humans because of a variety of routes of administration. Inorganic mercury (iHg) binds to thiol groups of proteins and enzymes in one’s body or is methylated by microorganisms. Organic form of Hg, contrary to the iHg, is more stable but may be demethylated to Hg²⁺ in the tissue of intestinal flora. Selenium (Se) also occurs in a variety of chemical forms in one’s body but both of these elements behave very differently from one another. Mercury binding to selenide or Se-containing ligands is a primary molecular mechanism that reduces toxicity of Hg. Complexes formed in such a way are irreversible, and thus, biologically inactive. Se deficiency in a human body may impair normal synthesis of selenoproteins and its expression because expression of mRNA may be potentially regulated by the Se status. This paper provides a comprehensive review concerning Hg–Se reciprocal action as a potential mechanism of protective action of Se against Hg toxicity as well as a potential detoxification mechanism. Although interactions between Hg–Se have been presented in numerous studies concerning animals and humans, we have focused mainly on animal models so as to understand molecular mechanisms responsible for antagonism better. The review also investigates what conclusions have been drawn by researchers with respect to the chemical species of Se and Hg (and their relationship) in biological systems as well as genetic variations and expression and/or activity of selenoproteins related to the thioredoxin (thioredoxin Trx/TrxR) system and glutathione metabolism. Int J Occup Med Environ Health 2018;31(5):575–592