The cyclin-dependent kinase inhibitor p27^Kip1 controls cell proliferation in response to normal mitogenic stimuli. We show here that p27^Kip1 also safeguards against excessive cell proliferation in specific pathophysioiogic settings. We used experimental glomerulonephritis as a paradigm for immune mediated inflammation and ureteral obstruction as a model for non-immune mediated inflammation. Renal function was substantially decreased in nephritic p27^−/− mice compared with control mice, and this was associated with increased glomerular cell proliferation, apoptosis and matrix protein accumulation. Tubular epithelial cell proliferation and apoptosis was also increased in p27^−/− mice following ureteral obstruction. p27^Kip1 may have a general role in protecting cells and tissues from inflammatory injury.