Primary open-angle glaucoma, the most common form of glaucoma, is characterized by irreversible loss of axons from the optic nerve. Previous research in humans and monkeys with glaucoma suggests that the site of damage to the axons is at the level of the lamina cribrosa in the optic nerve head. In the glaucomatous optic nerve head, progressive cupping of the optic disc results from compression, stretching, and remodeling of the connective tissue (extracellular matrix) of the lamina cribrosa. Astrocytes are the major cell type in the optic nerve and may participate actively in the remodeling of the extracellular matrix. There may be individual variability in the composition, structure, or reactive processes of the tissue supporting the axons in the optic nerve that may explain the variations in the nature and degree of cupping in response to intraocular pressure and in the progression of the neuropathy. We present evidence of specific changes in the extracellular matrix of the lamina cribrosa and the role of astrocytes in glaucomatous optic neuropathy. Future studies focused on developing therapies directed at preventing or controling damage to the extracellular matrix may help improve the outcome of the management of glaucoma.