Abstract: Endoplasmic reticulum (ER) stress plays an important role in the maintenance of ER homeostasis. Recently, more research has shown that a unique role has been speculated for ER stress in the pathogenesis of diabetes mellitus (DM) and its complications. Recent studies have also shown that ER stress is an early event associated with diabetic cardiomyopathy and may be triggered by hyperglycemia, free fatty acids (FFAs) and inflammation. In this mini-review we attempted to discuss the activation mechanism for ER stress in response to these triggers en route to disrupted ER functions and cellular autophagy or apoptosis, which ultimately induces insulin resistance and development of diabetic cardiomyopathy.