Glaucoma is a neurodegenerative disease of the retina characterized by the irreversible loss of retinal ganglion cells (RGCs), leading to visual loss. The main events in glaucoma pathogenesis include RGC death, loss of their axons, and damage/remodeling of the lamina cribrosa. RGC death is triggered by various risk factors, including elevated intraocular pressure (IOP), age, ocular biomechanics, and low ocular perfusion pressure. While elevated IOP is a major risk factor and the only currently treatable factor, many patients continue to experience disease progression despite IOP control. Other factors, such as oxidative stress, neurotrophin deprivation, mitochondrial dysfunction, ischemia/hypoxia, and neuroinflammation, may also contribute to RGC death in cases of non-elevated IOP. The underlying mechanisms of glaucomatous neurodegeneration include ischemia/hypoxia, mitochondrial dysfunction, oxidative stress, and neuroinflammation. In glaucoma, the immune system is involved, with glial cells, microglia, astrocytes, and Müller cells playing a key role in immunoregulation. Increased IOP activates glial cells in the retina, leading to a proinflammatory state that disrupts the blood-retinal barrier and causes RGC death. Modulating the immune response and glial cell activation represents an interesting new approach in glaucoma treatment. Glaucoma is a multifactorial disease involving the interaction of various molecular mechanisms that can induce the onset and progression of the pathology. Genetic factors, such as mutations in the MYOC, OPTN, and TBK1 genes, are associated with familial and congenital forms of glaucoma. Additionally, microRNAs (miRNAs) play a key role in regulating processes such as apoptosis, autophagy, neurogenesis, and neuroinflammation in glaucoma. Neuroinflammation is a key aspect of glaucoma pathogenesis, involving the activation of glial cells, the release of proinflammatory cytokines, and the recruitment of peripheral immune cells. Glial cell activation, particularly in the form of gliosis, is a critical response to damage and is associated with the progression of neurodegenerative processes. Microglia and astrocytes are the primary cells involved in neuroinflammation, with different activation phenotypes contributing to either neuroprotection or neurotoxicity. The morphological and molecular changes in glial cells during activation are closely linked to the severity of neuroinflammation and the progression of glaucoma. The balance between pro- and anti-inflammatory responses is crucial in determining the outcome of glaucomatous neurodegeneration.Glaucoma is a neurodegenerative disease of the retina characterized by the irreversible loss of retinal ganglion cells (RGCs), leading to visual loss. The main events in glaucoma pathogenesis include RGC death, loss of their axons, and damage/remodeling of the lamina cribrosa. RGC death is triggered by various risk factors, including elevated intraocular pressure (IOP), age, ocular biomechanics, and low ocular perfusion pressure. While elevated IOP is a major risk factor and the only currently treatable factor, many patients continue to experience disease progression despite IOP control. Other factors, such as oxidative stress, neurotrophin deprivation, mitochondrial dysfunction, ischemia/hypoxia, and neuroinflammation, may also contribute to RGC death in cases of non-elevated IOP. The underlying mechanisms of glaucomatous neurodegeneration include ischemia/hypoxia, mitochondrial dysfunction, oxidative stress, and neuroinflammation. In glaucoma, the immune system is involved, with glial cells, microglia, astrocytes, and Müller cells playing a key role in immunoregulation. Increased IOP activates glial cells in the retina, leading to a proinflammatory state that disrupts the blood-retinal barrier and causes RGC death. Modulating the immune response and glial cell activation represents an interesting new approach in glaucoma treatment. Glaucoma is a multifactorial disease involving the interaction of various molecular mechanisms that can induce the onset and progression of the pathology. Genetic factors, such as mutations in the MYOC, OPTN, and TBK1 genes, are associated with familial and congenital forms of glaucoma. Additionally, microRNAs (miRNAs) play a key role in regulating processes such as apoptosis, autophagy, neurogenesis, and neuroinflammation in glaucoma. Neuroinflammation is a key aspect of glaucoma pathogenesis, involving the activation of glial cells, the release of proinflammatory cytokines, and the recruitment of peripheral immune cells. Glial cell activation, particularly in the form of gliosis, is a critical response to damage and is associated with the progression of neurodegenerative processes. Microglia and astrocytes are the primary cells involved in neuroinflammation, with different activation phenotypes contributing to either neuroprotection or neurotoxicity. The morphological and molecular changes in glial cells during activation are closely linked to the severity of neuroinflammation and the progression of glaucoma. The balance between pro- and anti-inflammatory responses is crucial in determining the outcome of glaucomatous neurodegeneration.