The endothelin system is reported to play a significant role in glomerular and tubulointerstitial kidney disease. In the kidney, endothelins are produced in mesangial cells and the glomerular basement membrane by the endothelium and podocytes. The endothelin system regulates glomerular function by inducing proliferation, increasing permeability and in effect proteinuria, and stimulating inflammation, tubular fibrosis, and glomerular scarring. Endothelin A receptor antagonists have been proven to delay the progression of chronic kidney disease and play a protective role in immunoglobulin A nephropathy, focal segmental glomerulosclerosis, and diabetic nephropathy. There are several ongoing research studies with ETAR antagonists in nondiabetic nephropathy, Alport disease, vasculitis and scleroderma nephropathy, which results are promising. Some reports suggest that the endothelin system might contribute to ischemia–reperfusion injury, acute graft rejection and deterioration of graft function. Endothelin inhibition in renal transplantation and its influence on graft survival is the future direction needing further research. The most frequent side effects associated with ETAR antagonists is fluid retention. Additionally, it should be considered if selective ETAR antagonists therapy needs to be co-administered with sodium-glucose co-transporter 2 inhibitors, renin–angiotensin–aldosterone inhibitors or diuretics and which patients should be recruited to such treatment to minimize the risk of adverse outcomes.