Reactive oxygen species (ROS) are postulated to be a common trigger of insulin resistance. For example, treatment of adipocytes with either tumor-necrosis factor-α or dexamethasone increases ROS before impairing glucose uptake. Similarly, treatment with mitochondria-specific antioxidants preserves insulin sensitivity in animal models of insulin resistance. However, it remains unclear whether ROS contribute to insulin resistance in humans. First-degree relatives (FDRs) of type 2 diabetes subjects are at increased risk of developing insulin resistance and type 2 diabetes. Here we review the documented metabolic impairments in FDRs that could contribute to insulin resistance via increased oxidative stress. We propose that lipotoxic intermediates and lipid peroxides in skeletal muscle interfere with insulin signaling and might cause insulin resistance in these 'at risk' individuals.