Energy has been proposed to play a role in the ability of cells and tissues to defend against oxidative stress, even though the ultimate antioxidant capacity of a tissue is determined by the supply of reducing equivalents. The pathways involved in supplying reducing equivalents in response to an oxidative stress remain unclear, particularly if competing reactions such as ATP synthesis are active. Glutathione (GSH), a major component of cellular antioxidant systems, is maintained in the reduced form by glutathione reductase. Although this enzyme is specific for NADPH, the ability of intact cells, isolated mitochondria (which are a major source of free radicals and contain antioxidant systems independent of the rest of the cell), and whole tissues to supply reducing equivalents and maintain normal levels of GSH appears to involve NADH. This article reviews available data regarding the source and pathways by which reducing equivalents are made available to reduce exogenous oxidants, and suggests energy is not a factor. An improved understanding of the mechanism by which reducing equivalents are supplied by tissues to respond to an oxidative stress may direct future research toward designing strategies for augmenting the ability of tissues to defend themselves against oxidative stress induced by reperfusion or xenobiotics.