Morphological changes of the tubulointerstitial architecture are a major determinant in the progression of chronic renal disease. The evolution of the tubulointerstitial lesion includes early tubular hypertrophy, recruitment of inflammatory cells into the tubulointerstitial space, and proliferation of interstitial fibroblasts resulting in the irreversible changes of tubular atrophy and tubulointerstitial fibrosis. Many of these diverse effects are mediated by autocrine or paracrine release of growth factors, cytokines, and chemokines. Proteinuria, reduction in functional renal mass per se, alterations in tubular fluid reabsorption, and well as hemodynamic changes in the injured kidney may all stimulate local release of such growth factors. A more recent conception is that vasoactive substances, traditionally viewed to be only involved in the regulation of vascular tone, could actually mediate many of these functions of the more 'classical’ growth factors and cytokines. In this regard, one of the most intensively studied vasoactive substances is angiotensin II which has been linked to the progression of renal disease by a host of mechanisms, including the induction of tubular hypertrophy and proliferation of interstitial fibroblasts. There is also increasing evidence that other vasoconstrictive factors such as endothelins and eicosanoids are involved in pathophysiological changes leading eventually to tubulointerstitial fibrosis. On the other hand, natriuretic peptides may exert antifibrogenic properties. Although interference with the renin angiotensin system is currently the only treatment being effective in attenuating the loss of function in patients with chronic renal insufficiency, it is likely that future studies will also investigate the role of other vasoactive substances in the progression of human chronic renal disease.