The involvement of chemokines in inflammation is well established but their functional role in disease progression, and particularly in the development of fibrosis, is not yet understood. We have investigated the functional role that the chemokines monocyte chemotactic protein-1 (MCP-1) and RANTES play in inflammation and the progression to fibrosis during crescentic nephritis. During this disease inflammatory infiltrates are observed within glomeruli and interstitium in conjunction with increased expression of MCP-1 and RANTES and a decrease in renal function. Disease progression is marked by formation of glomerular crescents and the deposition of type I collagen. Blocking the function of MCP-1 or RANTES resulted in significant decreases in proteinuria as well as numbers of infiltrating leukocytes, indicating that both MCP-1 and RANTES play an important role in the inflammatory phase of crescentic nephritis. In particular, neutralization of MCP-1, but not RANTES, resulted in a dramatic decrease in glomerular crescent formation and deposition of type I collagen. These results highlight a novel role for MCP-1 in crescent formation and development of interstitial fibrosis and indicate that in addition to recruiting inflammatory cells this chemokine is critically involved in irreversible tissue damage.