Interstitial fibrosis is the common endpoint of end-stage chronic kidney disease (CKD) leading to kidney failure. The clinical course of many renal diseases, and thereby of CKD, is highly variable. One of the major challenges in deciding which treatment approach is best suited for a patient but also in the development of new treatments is the lack of markers able to identify and stratify patients with stable versus progressive disease. At the moment renal biopsy is the only means of diagnosing renal interstitial fibrosis. Novel biomarkers should improve diagnosis of a disease, estimate its prognosis and assess the response to treatment, all in a non-invasive manner. Existing markers of CKD do not fully and specifically address these requirements and in particular do not specifically reflect renal fibrosis. The aim of this review is to give an insight of the involvement of the extracellular matrix (ECM) proteins in kidney diseases and as a source of potential novel biomarkers of renal fibrosis. In particular the use of the protein fingerprint technology, that identifies neo-epitopes of ECM proteins generated by proteolytic cleavage by proteases or other post-translational modifications, might identify such novel biomarkers of renal fibrosis.