The relentless progression of many renal diseases to end-stage renal failure after an apparently transient initial insult remains an enigma that continues to fascinate nephrologists. The “hyperfiltration” hypothesis based on the rat remnant kidney model of nephron ablation provided much of the intellectual stimulus to the study of glomerular injury and scarring in the progression of renal disease [1]. While this may have some relevance to human renal disease progression [2], the early work of Risdon et al [3], Schainuck et al [4] and Bohle et al [5] has made it clear that, perhaps paradoxically, it is the degree of tubulointerstitial pathology that correlates most closely with declining renal function even in classical “glomerular” diseases. Belated recognition has now given rise to a new interest in the pathological processes occurring in the tubulointerstitial compartment of the diseased kidney. In this paper, we review briefly the histopathological evidence for the involvement of the tubulointerstitium in progressive renal disease and discuss potential mechanisms for tubulointerstitial injury. We also discuss pathways via which tubulointerstitial disease may lead to loss of glomerular function and propose a unifying hypothesis which links the two, taking into account much of the known experimental evidence at present.