Reactive oxygen species (ROS) contribute to the progression of various human diseases, including type 2 diabetes mellitus (T2DM). ROS can suppress the insulin response and contribute to the development of insulin resistance, a key pathological feature of T2DM. Paradoxically, ROS generated by NADP(H) oxidases at the plasma membrane and endomembranes might also be required for normal intracellular signaling. Growth factors, cytokines and hormones such as insulin promote the generation of ROS for the coordinated inactivation of protein tyrosine phosphatases and the promotion of tyrosine phosphorylation-dependent signaling. A recent study has established the potential of H₂O₂ to enhance insulin sensitivity in vivo and attenuate the development of insulin resistance. Thus, ROS have the capacity to both promote and attenuate the insulin response. Here I review evidence indicating that ROS promote insulin sensitivity versus insulin resistance and discuss the potential complications associated with the widespread use of antioxidants.