Oxidative stress is an important factor in the development of type 2 diabetes (T2D) and associated complications. Unfortunately, most clinical studies have failed to provide sufficient evidence regarding the benefits of antioxidants (AOXs) in treating this disease. Based on the known complexity of reactive oxygen species (ROS) functions in both the physiology and pathophysiology of glucose homeostasis, it is suggested that inappropriate dosing leads to the failure of AOXs in T2D treatment. To support this hypothesis, the role of oxidative stress in the pathophysiology of T2D is described, together with a summary of the evidence for the failure of AOXs in the management of diabetes. A comparison of preclinical and clinical studies indicates that suboptimal dosing of AOXs might explain the lack of benefits of AOXs. Conversely, the possibility that glycemic control might be adversely affected by excess AOXs is also considered, based on the role of ROS in insulin signaling. We suggest that AOX therapy should be given in a personalized manner according to the need, which is the presence and severity of oxidative stress. With the development of gold-standard biomarkers for oxidative stress, optimization of AOX therapy may be achieved to maximize the therapeutic potential of these agents.