The Free Radical or Oxidative Stress Theory of Aging is one of the most popular theories in aging research and has been extensively studied over the past several decades. However, recent evidence using transgenic/knockout mice that overexpress or down-regulate antioxidant enzymes challenge the veracity of this theory since the animals show no increase or decrease in lifespan. These results seriously call into question the role of oxidative damage/stress in the aging process in mammals. Therefore, the theory requires significant modifications if we are to understand the relationship between aging and the regulation of oxidative stress. Our laboratory has been examining the impacts of thioredoxins (Trxs), in the cytosol and mitochondria, on aging and age-related diseases. Our data from mice that are either up-regulating or down-regulating Trx in different cellular compartments, that is, the cytosol or mitochondria, could shed some light on the role of oxidative stress and its pathophysiological effects. The results generated from our lab and others may indicate that: 1) changes in oxidative stress and the redox state in the cytosol, mitochondria or nucleus might play different roles in the aging process; 2) the role of oxidative stress and redox state could have different pathophysiological consequences in different tissues/cells, for example, mitotic vs. post-mitotic; 3) oxidative stress could have different pathophysiological impacts in young and old animals; and 4) the pathophysiological roles of oxidative stress and redox state could be controlled through changes in redox-sensitive signaling, which could have more diverse effects on pathophysiology than the accumulation of oxidative damage to various molecules. To critically test the role of oxidative stress on aging and age-related diseases, further study is required using animal models that regulate oxidative stress levels differently in each cellular compartment, each tissue/organ, and/or at different stages of life (young, middle and old) to change redox sensitive signaling pathways.