<p>Extracellular Matrix (ECM) is a dynamic, multi-functional macromolecular scaffold providing structural support that participates in tissue structure, signalling, and homeostasis. Apart from its role as a scaffold, the ECM has been recognized as a regulator of tissue homeostasis, disease, and response to therapy. Abnormalities in ECM remodeling have been associated with cancer, fibrosis, cardiovascular disease, and neurodegenerative disorders. Current progress emphasizes the diagnostic and therapeutic value of ECM-based biomarkers, ECM-targeted imaging, and approaches that target the remodeling and mechanical properties of the matrix. At the same time, ECM biomaterials, organoids, and bioprinted systems allow for patient-specific and physiologically relevant models of tissue. ECM-focused omics and modeling tools are emerging. In contrast to previous reviews that emphasize either ECM composition or disease-specific remodelling, this review combines ECM diagnostics, therapeutic targeting strategies, regenerative approaches, and computational models from a single precision medicine viewpoint. The major challenges in this area are ECM heterogeneity, the poor translation of ECM-targeted therapies to the clinic, and the absence of standardized diagnostic assays. Finally, we will discuss the future directions of the field over the next five to ten years.</p> Graphical abstract <p></p>