Introduction: Glaucoma is a neurodegenerative disease that causes irreversible blindness worldwide. It results from retinal ganglion cell (RGC) loss and progressive optic nerve damage, mainly associated with elevated intraocular pressure (IOP). Current treatments focus on reducing IOP but do not directly delve into the underlying pathophysiological mechanisms of neurodegeneration. A mechanistic approach enables researchers to identify drugs that target these fundamental mechanisms rather than solely addressing symptoms such as elevated IOP. Areas covered: This review explores mechanistic approaches to emerging preclinical agents, including those targeting trabecular meshwork function, neuroprotection, RGC survival, and ocular blood flow. We also review promising nutrients, gene therapies, and biologics currently under investigation, particularly agents that modulate oxidative stress and neuroinflammatory pathways. Expert opinion: Recently, investigational drugs that protect the RGC and the optic nerve from further damage have become critical in treating glaucoma. For example, CNTF was shown to promote the survival and growth of photoreceptors and RGC in cell culture and animal models. Moreover, optimizing drug delivery is paramount to achieving tailored management and patient adherence. Meticulous clinical trials will pave the way for the potential reevaluation of glaucoma management, offering new hope for patients with this complex disease.