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Low-molecular-mass selenium (LMM-Se) molecules, such as ebselen and diphenyldiselenide, have many biological and potential therapeutic activities; however, little is known about their mechanism of action. It has been stipulated that LMM-Se can modify the physiological chemistry of endogenous thiol (–SH) and selenol (–SeH) groups by different mechanisms. Generically, LMM-Se compounds are poor mimetics of glutathione peroxidase (GPx) enzyme, suggesting that their thiol-modifier effect is more reasonable to justify their biological action. Unfortunately, the LMM-Se interactions with their targets are relatively non-specific. Here, the action of LMM-Se as potential therapeutic agents will be discussed, as well as the bottleneck and myths about their potential use as therapeutic agents.