Diabetic nephropathy (DN) is the major cause of chronic kidney disease (CKD) which normally leads to end stage renal disease (ESRD) or dialysis. Despite vigorous management including treatment of hypertension, glyceamic control and the utilization of inhibitors of renin angiotensin system (RAS), a significant proportion of diabetic patients still develop CKD and progress to ESRD. Advances in understanding of the pathogenesis and pathology of DN have made it clear that DN occurs as a result of imbalance between causative factors and endogenous protective factors. To emphasize this concept, this review will focus on some of the current knowledge concerning both causative and endogenous protective factors of DN.