Reactive oxygen species are produced by various stressors derived from internal and external sources, including endogenous metabolic activities. Glucose metabolism is one of the most primitive sources for energy production for most cells; however, it may at the same time yield hazardous oxidative stress via simultaneous oxidant production. The protective mechanism against oxidative stress is thus an indispensable biological function. Recently, genetic mutation loci affecting life span were isolated from experimental model organisms, and several locus products were found to be closely linked with machinery either producing or defending oxidative stress. Thioredoxin (TRX) is a small protein having strong antioxiradical quenching capabilities and other multiple functions depending on the cellular redox state. In this review, we focus on the role of TRX in the aging process (senescence) as a redox-regulating molecule against oxidative stress. We also discuss the possibility of the TRX system serving as an index marker for cellular proliferation and senescence.