Despite remarkable advances in vitreoretinal surgery, proliferative vitreoretinopathy (PVR) remains a common cause of severe visual loss or blindness. One of the critical reasons for PVR‐induced blindness is tractional retinal detachment due to the formation of contractile preretinal fibrous membranes. This membrane formation is characterized by the proliferation and migration of cells and the excessive synthesis and deposition of extracellular matrix proteins. Herein we present the disease pathways of PVR, reviewing the role of both systemic and intraocular cells as well as molecular mediators. A chronological sequence of events leading to PVR is also hypothesized. Better understanding of the pathogenesis of PVR is needed in order to improve disease management. Efforts should be oriented towards greater cooperation between basic researchers and clinicians, aimed at matching the different clinical scenarios with the biological markers of the disease. J. Cell. Physiol. 229: 1577–1583, 2014. © 2014 Wiley Periodicals, Inc.