End-stage renal disease (ESRD) is characterized by the development of fibrotic lesions in the glomerular, interstitial and vascular compartments. Renal fibrogenesis, a common complication of diabetes and hypertension, is a complex dynamic process involving several players such as inflammatory agents, cytokines, vasoactive agents and enzymes participating in extracellular matrix assembly, anchoring or degradation. The only available treatment today against chronic renal failure is dialysis or kidney transplantation, making thus ESRD one of the most expensive diseases to treat on a per-patient basis. An emerging challenge for clinicians, maybe the nephrologist's Holy Grail in the 21st century, is to stop definitively the decline of renal function and, if possible, to achieve regression of renal fibrosis and restoration of renal structure. Over the last 5 years, different approaches have been tested in experimental models of nephropathy with variable degree of success. In this review, we will focus on the mechanisms of the hypertension-associated fibrosis and the few recent studies that gave promising results for a therapeutic intervention.