Treatment of posterior segment fibrosis is an unmet challenge in ophthalmology. Fibrotic responses complicate the pathology and treatment of age-related macular degeneration, diabetic retinopathy, retinal detachment, and other retinal diseases resulting in severe visual impairment. There is a lack of clear understanding of the exact mechanisms and different cell types taking part in retinal and preretinal fibrosis. This review discusses the current knowledge regarding various aspects of the intracellular signaling pathways impacting vitreoretinal fibrotic processes, focusing on the cellular and molecular mechanisms, summarizing the results of preclinical and clinical studies, and suggesting strategies for future investigations.