The mechanism(s) of the endothelin (ET) and reactive oxygen species pathways in conjunction with the nitric oxide (NO) pathway that promote and/or blunt the progression of diabetic kidney disease have been the focus of many laboratories' efforts to reveal new therapeutic targets. In both animal models and patients with diabetic nephropathy, pharmacological blockade of ET receptors results in a significant reduction. However, edema has been documented as a persistent side effect. It is unclear whether selective ET(A) antagonists or nonselective ET(A/B) antagonists are preferred in diabetic conditions. We have proposed that ET(B) activates the NO pathway to blunt diabetes-induced nephropathy such that ET(A) selectivity should be more efficacious. The NO pathway in diabetes facilitates vascular dysfunction while in the renal tubular system, NO serves to blunt disease progression. NO synthase isoform activity is also critically regulated in diabetic kidney disease within the renal vascular and tubular systems through a complex interaction with reactive oxygen species. We will examine the complexities of the ET and NO pathways in diabetic kidney disease to propose novel mechanisms for future investigation. Copyright © 2011 S. Karger AG, Basel.