Despite new and effective drug therapies, insulin resistance (IR), type 2 diabetes mellitus (T2D) and its complications remain major medical challenges. It is accepted that IR, often associated with over-nutrition and obesity, results from chronically elevated oxidant stress (OS) and chronic inflammation. Less acknowledged is that a major cause for this inflammation is excessive consumption of advanced glycation end products (AGEs) with the standard western diet. AGEs, which were largely thought as oxidative derivatives resulting from diabetic hyperglycemia, are increasingly seen as a potential risk for islet β-cell injury, peripheral IR and diabetes. Here we discuss the relationships between exogenous AGEs, chronic inflammation, IR, and T2D. We propose that under chronic exogenous oxidant AGE pressure the depletion of innate defense mechanisms is an important factor, which raises susceptibility to inflammation, IR, T2D and its complications. Finally we review evidence on dietary AGE restriction as a nonpharmacologic intervention, which effectively lowers AGEs, restores innate defenses and improves IR, thus, offering new perspectives on diabetes etiology and therapy.