Imperfect attempts at organ repair after repeated injury result in aberrant formation of extracellular matrix (ECM) and loss of tissue structure. This abnormal ECM goes from being a consequence of cellular dysregulation to become the backbone of a persistently fibrotic cell niche that compromises organic function and ultimately drives systemic disease. Here, we review our current understanding of the structure of the ECM, the mechanisms behind organ-specific fibrosis, resolution, healing and regeneration, as well as the development of anti-fibrotic strategies. We also discuss the design of biomarkers to investigate fibrosis pathophysiology, track fibrosis progression, systemic damage, and fibrosis resolution.