The incidence of chronic kidney diseases (CKD) is constantly rising, reaching epidemic proportions in the western world and leading to an enormous threat, even to modern health-care systems, in industrialized countries. Therapies of CKD have greatly improved following the introduction of drugs targeting the renin-angiotensin system (RAAS) but even this refined pharmacological approach has failed to stop progression to end-stage renal disease (ESRD) in many individuals. In vitro historical data and recent new findings have suggested that progression of renal fibrosis might occur as a result of an altered tubulo-interstitial microenvironment and, more specifically, as a result of an altered epithelial-mesenchymal crosstalk. Here we the review biological findings that support the hypothesis of an altered cellular crosstalk in an injured local tubulo-interstitial microenvironment leading to renal disease progression. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.