Involvement of the renin–angiotensin system (RAS) in human pathophysiology has expanded to include several diseases beyond a traditional role in salt and water homeostasis. In diabetes, there is significant overactivity of the RAS, which is inhibited by treatment with RAS blockers, thus decreasing diabetic complications. Activation of the RAS in diabetes includes several unique aspects, such as elevation of circulating prorenin levels and angiotensin (Ang) II-independent effects, mediated through interaction of pro(renin), with the pro(renin) receptor. Ang II-independent RAS actions suggest that efficacy of angiotensin receptor blockers (ARBs) and ACE inhibitors would have limitations in the treatment of diabetic patients. Recent meta-analyses of clinical trials have suggested that currently used RAS blockers may not provide additional benefits in diabetics compared to non-diabetics. We recently reported another novel aspect of the RAS, the intracellular system, which is dramatically activated in hyperglycemic conditions. In cardiac myocytes and fibroblasts, we demonstrated the presence of RAS components and synthesis of Ang II intracellularly. Hyperglycemia selectively upregulated the intracellular system in cardiac myocytes, vascular smooth muscle cells (VSMC), and renal mesangial cells where Ang II synthesis was largely catalyzed by chymase, not ACE. We also demonstrated elevation of intracellular Ang II (iAng II) levels in diabetic rat hearts, which resulted in increased cardiac myocyte apoptosis, oxidative stress, and cardiac fibrosis, suggesting a significant role of iAng II in diabetic cardiomyopathy. Others and we have previously reported that iAng II elicits multiple biological effects, some of which are not blocked by ARBs. Using Chinese hamster ovary (CHO) cells that do not express AT₁ receptor, we confirmed that the latter are not required for intracellular actions of Ang II. The AT₁-independent effects of iAng II are likely mediated by novel interactions between Ang II and intracellular proteins. The mechanism of RAS activation and intracellular accumulation of components by cardiac myocytes in high glucose (HG) conditions is not known. There is a possibility that an increased influx of glucose into the hexosamine biosynthesis pathway (HBP) and resultant O-glycosylation of proteins/transcription factors is responsible for the activation of the RAS and intracellular synthesis of Ang II.