BACKGROUND: While glaucoma is the most common cause of optic disc cupping, it can also be seen in a number of congenital and acquired optic neuropathies. It behooves both glaucoma and neuro-ophthalmic specialists to be able to differentiate glaucoma from neurological conditions, which give a similar ophthalmoscopic appearance to the optic disc. EVIDENCE ACQUISITION: This review is a combination of the authorsEclinical experience from tertiary glaucoma and neuro-ophthalmology referral centers, combined with a literature review using PubMed. RESULTS: Even for experienced observers, differentiation between glaucomatous and nonglaucomatous cupping can be difficult. In the majority of cases, this distinction can be made following a careful clinical examination combined with a variety of imaging techniques. Possible mechanisms, which lead to changes in optic disc morphology, are reviewed. CONCLUSIONS: Differentiating glaucomatous from nonglaucomatous optic disc cupping can be a formidable challenge for the clinician. Examination of the patient combined with imaging of the retinal nerve fiber layer and optic disc topography provides a basis to resolve this clinical conundrum.