Various disciplines within nephrology investigate the mechanisms by which kidneys fail. Progress in the areas of glomerular hemodynamics, proteinuria, tubular biology, interstitial nephritis, fibroblast formation, and fibrosis have added kernels of information that together support a unified theory of renal progression. Prevention of progression to end-stage disease has largely focused on control of systemic and glomerular hypertension. Current success in delaying a decline in glomerular filtration rate underlines the promise of a more comprehensive approach. New knowledge about the cell biology of progression also suggests that other adjunctive therapies may be possible. We describe the progress and highlight those spheres where new-targeted interventions may arise.