Microvascular complications are responsible for a major proportion of the burden associated with diabetes contributing to substantial morbidity, mortality, and healthcare burden in people with diabetes. Retinopathy, nephropathy, and neuropathy constitute the leading causes of blindness, end-stage renal disease, and lower-extremity amputations, respectively. Since the efficacy of causal therapies of diabetic microvascular complications is limited, especially in type 2 diabetes, there is an unmet need for adjunct treatments which should be effective despite ongoing hyperglycemia. Experimental studies have indicated that diabetic microvascular complications can be prevented or ameliorated by various biofactors in animal models by interfering with the pathophysiology of the underlying condition. Some of the findings related to biofactors, like α-lipoic acid and benfotiamine, could be translated into the clinical arena and confirmed in clinical trials, especially in those focusing on diabetic polyneuropathy. Given the micronutrient nature of these compounds, their safety profile is excellent. Thus, they have the potential to favorably modify the natural history of the underlying complication, but long-term clinical trials are required to confirm this notion. Ultimately, biofactors should expand our therapeutic armamentarium against these common, debilitating, and even life-threatening sequelae of diabetes.