A central event in tissue remodeling is expression and activation of extracellular matrix (ECM)–degrading proteinases and collagenases, resulting in the release of small protein fragments called neoepitopes into the circulation. These neoepitopes can and are being targeted as biochemical markers of “end products of tissue destruction.” Neoepitopes can include different posttranslational modifications (PTMs) such as citrullination, nitrosylation, glycosylation, and isomerization. Each modification is a result from specific and local physiological processes. Identification of PTMs on neoepitopes may deliver unique disease-specific biomarkers and have been identified in musculoskeletal, cardiovascular, fibrotic, and neurodegenerative diseases. The neoepitope biomarkers relying on analytes that are modified by multiple PTMs may become optimal tools that meet the burden of disease, investigatory, prognostic, efficacy of intervention and diagnosis (BIPED) biochemical marker “usefulness” criteria. In this chapter, the use of structural biomarkers is discussed, with emphasis on various PTMs in different disease indications. The use of the BIPED criteria is likewise discussed, as well as the importance of understanding the effect of the matrix in which the biomarker is measured, such as serum, urine, and other body fluids, on interpretation of results.