Tumor cell proliferation, de-differentiation, and progression depend on a complex combination of altered intracellular processes including cell cycle regulation, excessive growth factor pathway activation, and decreased apoptosis. Metabolites from these processes result in significant cellular oxidative stress that must be buffered to prevent permanent cell damage and cell death. Tumor cells depend on a complex set of respiratory pathways to generate the necessary energy as well as redox-sensitive pro-survival signaling pathways and factors to cope with and defend against the detrimental effects of oxidative stress. It has been hypothesized that redox-sensitive signaling factors such as thioredoxin reductase-1 (TR) and thioredoxin (TRX) may represent central pro-survival factors that would allow tumor cells to evade the damaging and potentially cytotoxic effects of endogenous and exogenous agents that induce oxidative stress. The overarching theme of this review is an extension of the hypothesis that tumor cells use these redox sensitive pro-survival signaling pathways/factors, which are up-regulated due to increased tumor cell respiration, to evade the cytotoxic effects of anticancer agents. These observations suggest that redox-sensitive signaling factors may be potential novel molecular targets for drug discovery.