Millions of people worldwide suffer from retinal disorders. Retinal diseases require prompt attention to restore function or reduce progressive impairments. Genetics, epigenetics, life-styling/quality and external environmental factors may contribute to developing retinal diseases. In the physiological retina, some glial cell types sustain neuron activities by guaranteeing ion homeostasis and allowing effective interaction in synaptic transmission. Upon insults, glial cells interact with neuronal and the other non-neuronal retinal cells, at least in part counteracting the biomolecular changes that may trigger retinal complications and vision loss. Several epigenetic and oxidative stress mechanisms are quickly activated to release factors that in concert with growth, fibrogenic and angiogenic factors can influence the overall microenvironment and cell-to-cell response. Reactive Müller cells participate by secreting neurotrophic/growth/angiogenic factors, cytokines/chemokines, cytotoxic/stress molecules and neurogenic inflammation peptides. Any attempt to maintain/restore the physiological condition can be interrupted by perpetuating insults, vascular dysfunction and neurodegeneration. Herein, we critically revise the current knowledge on the cell-to-cell and cell-to-mediator interplay between Müller cells, astrocytes and microglia, with respect to pro-con modulators and neuroprotective/detrimental activities, as observed by using experimental models or analyzing ocular fluids, altogether contributing a new point of view to the field of research on precision medicine.