Transforming growth factor-β (TGF-β) may play a role in the pathogenesis of primary open-angle glaucoma (POAG). Elevated levels of TGF-β are found in the aqueous humor and in reactive optic nerve astrocytes in patients with glaucoma. In POAG, aqueous humor outflow resistance at the trabecular meshwork (TM) leads to increased intraocular pressure and retinal ganglion cell death. It is hypothesized that TGF-β increases outflow resistance by altering extracellular matrix homeostasis and cell contractility in the TM through interactions with other proteins and signaling molecules. TGF-β may also be involved in damage to the optic nerve head. Current available therapies for POAG focus exclusively on lowering intraocular pressure without addressing extracellular matrix homeostasis processes in the TM. The purpose of this review is to discuss possible therapeutic strategies targeting TGF-β in the treatment of POAG. Herein, we describe the current understanding of the role of TGF-β in POAG pathophysiology, and examine ways TGF-β may be targeted at the levels of production, activation, downstream signaling, and homeostatic regulation.