Upper urinary tract obstruction, regardless of its cause, often poses a significant clinical challenge to the urologist. Renal cellular and molecular events that occur in response to upper urinary tract obstruction result in a progressive and permanent loss in renal function when left untreated. These pathologic changes include the development of renal fibrosis, tubular atrophy, interstitial inflammation, and apoptotic renal cell death. Several cytokines and growth factors have been identified as major contributors to obstruction-induced renal fibrosis and apoptotic cell death, most notably transforming growth factor-b1 (TGF-b1), angiotensin II, nuclear factor-kB (NF-kB), and tumor necrosis factor-a (TNF-a). This review examines the challenges of upper urinary tract obstruction and the role of these mediators in obstruction-induced renal injury.