The thioredoxin (Trx) system comprises Trx, truncated Trx (Trx-80), Trx reductase, and NADPH, besides a natural Trx inhibitor, the thioredoxin-interacting protein (TXNIP). This system is essential for maintaining the balance of the cellular redox status, and it is involved in the regulation of redox signaling. It is also pivotal for growth promotion, neuroprotection, inflammatory modulation, antiapoptosis, immune function, and atherosclerosis. As an ubiquitous and multifunctional protein, Trx is expressed in all forms of life, executing its function through its antioxidative, protein-reducing, and signal-transducing activities. In this review, the biological properties of the Trx system are highlighted, and its implications in several human diseases are discussed, including cardiovascular diseases, heart failure, stroke, inflammation, metabolic syndrome, neurodegenerative diseases, arthritis, and cancer. The last chapter addresses the emerging therapeutic approaches targeting the Trx system in human diseases.