Most cancer cells contain high levels of reactive oxygen species (ROS), which result in higher expression levels of the glutathione and thioredoxin reductase systems. These antioxidant systems convert ROS to nonharmful compounds and they also reduce disulfide bonds in oxidized proteins. They also control the glutathionylation and nitrosylation of proteins, which alters the activity of the proteins. Through these functions the upregulated antioxidant systems act on transcription factors and on signaling pathways, which result in the promotion of cancer cell growth and the prevention of cell apoptosis. High levels of certain members of the glutathione and thioredoxin systems in specific cancers correlate with poor patient prognosis and with drug resistance. Therefore, these antioxidants represent a potential new target for chemotherapy treatments, especially the thioredoxin reductase (TrxR) protein, which can be targeted through its selenocysteine residue. Inhibition of TrxR leads to increased ROS levels in cancer cells to a lethal level, consequently leading to activation of cell death mechanisms. However, ROS levels remain at nonlethal levels in normal cells, thus enabling specific targeting of cancer cells. The design and availability of inhibitors for the specific upregulated antioxidant proteins in each type of cancer may also overcome drug resistance by resensitizing cancers to existing chemotherapy treatments.