Fibrosis is defined by excessive formation and accumulation of extracellular matrix proteins, produced by myofibroblasts, that supersedes normal wound healing responses to injury and results in progressive architectural remodelling. Fibrosis is often detected in advanced disease stages when an organ is already severely damaged and can no longer function properly. Therefore, there is an urgent need for reliable and easily detectable markers to identify and monitor fibrosis onset and progression as early as possible; this will greatly facilitate the development of novel therapeutic strategies. Osteoprotegerin (OPG), a well-known regulator of bone extracellular matrix and most studied for its role in regulating bone mass, is expressed in various organs and functions as a decoy for receptor activator of nuclear factor kappa-B ligand (RANKL) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Recently, OPG has been linked to fibrosis and fibrogenesis, and has been included in a panel of markers to diagnose liver fibrosis. Multiple studies now suggest that OPG may be a general biomarker suitable for detection of fibrosis and/or monitoring the impact of fibrosis treatment. This review summarizes our current understanding of the role of OPG in fibrosis and will discuss its potential as a biomarker and/or novel therapeutic target for fibrosis.