Consisting of a defined set of extracellular proteins secreted from resident cells and with minor contributions from serum proteins, the extracellular matrix (ECM) is an essential component of all tissues. Maintaining tissue homeostasis, structural support and cellular control through cell-ECM communication, the ECM has come to be viewed as not just a passive structural entity but rather as a dynamic signaling conduit between cells and the extracellular compartment. Proteins and their cleavage products mediate this communication, and aberrant signaling, either directly or indirectly distorting the ECM, results in pathological conditions including cancer, inflammation, fibrosis, and neurodegenerative diseases. Characterization of ECM components, the matrisome, the extracellular environment and their changes in disease is therefore of importance to understand and mitigate by developing novel therapeutics. Liquid chromatography-mass spectrometry (LC-MS) proteomics has been integral to protein and proteome research for decades and long superseded the obsolescent gel-based approaches. A continuous effort has ensured progress with increased sensitivity and throughput as more advanced equipment has been developed hand in hand with specialized enrichment, detection, and identification methods. Part of this effort lies in the field of degradomics, a branch of proteomics focused on discovering novel protease substrates by identification of protease-generated neo-N termini, the N-terminome, and characterizing the responsible protease networks. Various methods to do so have been developed, some specialized for specific tissue types, others for particular proteases, throughput, or ease of use. This review aims to provide an overview of the state-of-the-art proteomics techniques that have successfully been recently utilized to characterize proteolytic cleavages in the ECM and thereby guided new research and understanding of the ECM and matrisome biology.