Glaucoma is a neurodegenerative disease and a worldwide leading cause of irreversible vision loss. In the last decades, high efforts have been made to develop novel treatments effective in inducing protection and/or recovery of neural function in glaucoma, including neurotrophic factors (NTFs). These approaches have shown encouraging data in preclinical setting; however, the challenge of sustained, targeted delivery to the retina and optic nerve still prevents the clinical translation. In this paper, the authors review and discuss the most recent advances for the use of NTFs treatment in glaucoma, including intraocular delivery. Novel strategies in drug and gene delivery technology for NTFs are proving effective in promoting long-term retinal ganglion cells (RGCs) survival and related functional improvements. Results of experimental and clinical studies evaluating the efficacy and safety of biodegradable slow-release NTF-loaded microparticle devices, encapsulated NTF-secreting cells implants, mimetic ligands for NTF receptors, and viral and non-viral NTF gene vehicles are discussed. NTFs are able to prevent and even reverse apoptotic ganglion cell death. Nevertheless, neuroprotection in glaucoma remains an open issue due to the unmet need of sustained delivery to the posterior segment of the eye. The recent advances in intraocular delivery systems pave the way for possible future use of NTFs in clinical practice for the treatment of glaucoma.