Thioredoxin and glutaredoxin systems in mammalian cells utilize thiol and selenol groups to maintain a reducing intracellular redox state acting as antioxidants and reducing agents in redox signaling with oxidizing reactive oxygen species. During the last decade, the functional roles of thioredoxin in particular have continued to expand, also including novel functions such as a secreted growth factor or a chemokine for immune cells. The role of thioredoxin and glutaredoxin in antioxidant defense and the role of thioredoxin in controlling recruitment of inflammatory cells offer potential use in clinical therapy. The fundamental differences between bacterial and mammalian thioredoxin reductases offer new principles for treatment of infections. Clinical drugs already in use target the active site selenol in thioredoxin reductases, inducing cell death in tumor cells. Thioredoxin and binding proteins (ASK1 and TBP2) appear to control apoptosis or metabolic states such as carbohydrate and lipid metabolism related to diseases such as diabetes and atherosclerosis.