Mesangial cells (MCs) play a central role in the physiology and pathophysiology of endothelin-1 (ET-1) in the kidney. MCs release ET-1 in response to a variety of factors, many of which are elevated in glomerular injury. MCs also express ET receptors, activation of which leads to a complex signaling cascade with resultant stimulation of MC hypertrophy, proliferation, contraction, and extracellular matrix accumulation. MC ET-1 interacts with other important regulatory factors, including arachidonate metabolites, nitric oxide, and angiotensin II. Excessive stimulation of ET-1 production by, and activity in, MC is likely of pathogenic importance in glomerular damage in the setting of diabetes, hypertension, and glomerulonephritis. The recent introduction of ET antagonists, and possibly ET-converting enzyme inhibitors, into the clinical arena establishes the potential for new therapies for those diseases characterized by increased MC ET-1 actions. This review will examine our present understanding of how ET-1 is involved in mesangial function in health and disease. In addition, we will discuss the status of clinical trials using ET antagonists, which have only been conducted in nonrenal disease, as a background for advocating their use in diseases characterized by excessive MC-derived ET-1.