The relative importance of mechanisms relevant to smoking-induced vascular injury is poorly understood. Cigarette smoke is a source of free radicals but also results in cellular activation and consequent generation of free radicals in vivo. Here we consider several approaches to estimating the consequences of free radical generation in vivo, using measurements of modified lipids, proteins, and DNA. Smoking appears to result in elevation of several biomarkers of oxidant stress, some in a dose-related fashion. There is also some evidence that disordered endothelial function in smokers may be partly attributable to oxidant stress. Other effects of smoking on hemostatic activation, sympathoadrenal function, and lipoprotein structure and function may also be modulated by smoking-induced oxidant stress. The emergence and application of rational quantitatively reliable indexes of oxidant stress in vivo is likely to elucidate the relative contribution of oxidant stress to smoking-induced vascular injury.