Enzymatically controlled levels of reactive oxygen species are key for all living cells, maintaining steady state concentrations compatible with life while at the same time allowing for physiological continuous fluctuations dictated by growth conditions as well as being required for several intracellular signaling pathways. The two main enzymatic intracellular reductive pathways in mammalian cells are the glutathione and thioredoxin systems, encompassing flavoprotein reductases (thioredoxin reductases and glutathione reductase) and thioredoxin-fold proteins including thioredoxin isoenzymes and glutathione-driven glutaredoxins. Together with downstream antioxidant enzymes such as peroxiredoxins, glutathione peroxidases and methionine sulfoxide reductases, these systems provide potent antioxidant power counteracting excessive levels of reactive oxygen species while ensuring fine regulation of signaling pathways. Interestingly, the thioredoxin reductases can also provide significant redox cycling activities coupled to oxygen, especially if their selenocysteine-containing active sites are compromised, thereby being converted to NADPH oxidases and thus instead contribute to an exaggerated oxidative stress. This dualism of thioredoxin reductases and its significance in cellular physiology, particularly as a consequence of electrophilic compounds targeting the selenocysteine residues and their conversion to NADPH oxidases, is the main topic of discussion in this chapter.