The aim of this review is to discuss the potential usefulness of novel biochemical markers of connective tissues: neo-epitopes of extracellular matrix proteins generated by post-translational modifications by tissue proteinases. As each modification results from a specific local physiological or pathobiological process, the identification of specific proteinase-mediated cleavage products of tissue-specific proteins may produce a unique disease-specific biochemical marker. The authors present a novel interpretation of the process of tissue degradation described by neo-epitope fragments of the interstitial and basement membrane matrix in fibrotic disease, and the diagnostic and prognostic potential of such markers. Moreover, the authors highlight the importance of matrix protein fragments not only as markers of tissue remodeling, but also as players in tissue remodeling, due to their signaling properties.