Exfoliation syndrome is the most common, identifiable cause of open-angle glaucoma. It is an age-related disorder of the extracellular matrix, characterized by excessive production and accumulation of deposits of fibrillar extracellular material in the ocular tissues. Exfoliation deposits are most commonly appreciated in the pupillary border and the anterior lens capsule. Ocular manifestations of exfoliation include angle-closure and open-angle glaucoma, cataract, lens subluxation, and central retinal vein occlusion. Exfoliation syndrome is associated with ocular and systemic hypoxia and apart from glaucoma, predisposes to capsular breaks, zonular dehiscence and vitreous loss during cataract surgery. This chapter describes the epidemiology of exfoliation and glaucoma, clinical features, pathophysiology of exfoliation, pathogenetic factors and key molecules and their role in exfoliation pathophysiology, pathogenetic concept of exfoliation syndrome, mechanisms of development of glaucoma, and management.