Diabetes mellitus (DM) is a serious health concern that affects millions of people worldwide. Despite numerous studies on the topic, the exact mechanisms underlying diabetes progression and its complications is still unclear. Growing evidence suggests that hyperglycemia results in increased reactive oxygen species (ROS) production, leading to oxidative stress which affects and damages various tissues and organs. Oxidative stress results from an imbalance between ROS and antioxidants. During cellular metabolism free radicals such as ROS and reactive nitrogen species (RNS) are produced, and these free radicals have dual effects (both positive and negative) on nearby tissues and activate several oxidative stress-related signaling pathways. Oxidative stress has been identified as a major player in the pathogenesis of diabetes and its associated complications such as stroke, neuropathy, retinopathy, peripheral vascular disease, nephropathy and lower limb ulceration. Oxidative stress damages the surrounding tissue, and the effects continue for extended periods even after blood glucose concentrations return to normal. Prolonged oxidative stress results in insulin resistance, β-cell dysfunction, glucose intolerance and mitochondrial damage. Antioxidants are a group of enzymatic or non-enzymatic molecules that encounter and neutralize free radicals, thereby protecting the body from oxidative stress. Many exogenous molecules such as antioxidant supplements, vitamins (vitamin C and E) and metal ion chelators detoxify free radicals and maintain physiological levels. A better understanding of the involvement of oxidative stress in the pathogenesis of diabetes could have major therapeutic implications for treatment. An effective approach to treat oxidative stress is by using exogenous drugs that mimic antioxidants. Overall, this chapter highlights the understanding of oxidative stressrelated mechanisms underlying the development of diabetes. It also elaborates on antioxidant therapy strategies to diminish oxidative stress and to treat diabetic associated complications.