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Exfoliation syndrome (XFS) is a systemic disease with significant ocular manifestations, including glaucoma and cataract. The disease impacts close to 70 million people globally and is now recognised as the most common identifiable cause of open-angle glaucoma. Since the discovery of XFS 100 years ago by Dr John G. Lindberg, there has been considerable advancement in understanding its pathogenesis and resulting clinical implications. The purpose of this paper is to summarise information regarding the epidemiology, pathophysiology, ocular manifestations and systemic associations of XFS with the objective of sharing clinical pearls to assist in early detection and enhanced management of patients.