Over the years, a very large amount of evidence has accumulated indicating that endothelin (ET)-1 is an important stimulus for inflammation. This is true for a wide range of organ system diseases, including chronic kidney disease. Nonetheless, our understanding of the role and mechanisms by which ET-1 promotes the activation of both the innate and adaptive immune systems is not understood. ET-1 can directly activate neutrophils as well as endothelial cells to stimulate production of chemoattractant factors, such as monocyte chemoattractant factor-1, and increase synthesis of cell adhesion molecules, such as soluble ICAM-1. The mechanisms that trigger these events, however, are less clear. Elevated blood pressure as well as hyperglycemia could be important factors that facilitate ET-1-dependent inflammation. While renal inflammation has not been used as an endpoint for drug development, the rationale for the use of ET antagonists as anti-inflammatory agents in chronic kidney disease is quite strong, based on animal studies and at least one study in humans with nondiabetic nephritis. While the preponderance of evidence suggests that ETA selective antagonists are advantageous over combined ETA/B receptor blockers, considerably more work needs to be done in order to understand the complex role of ET in renal inflammation.