The trabecular meshwork (TM) is a key regulator of intraocular pressure (IOP) through its role in facilitating aqueous humor outflow. Pathological alterations in the TM-such as reduced cellularity, impaired extracellular matrix turnover, and increased biomechanical stiffness-raise outflow resistance, leading to elevated IOP and contributing to glaucoma pathogenesis. We summarize the TM's anatomical structure, cellular heterogeneity, and biomechanical properties, emphasizing its central role in maintaining IOP homeostasis. It also outlines TM alterations across different glaucoma subtypes and highlights key molecular mechanisms underlying TM dysfunction, including dysregulation of Rho GTPase signaling, nitric oxide (NO) pathways, TGF-β2-induced fibrosis, lipid signaling, and endoplasmic reticulum stress. Advancements in TM-targeted therapies include pharmacologic interventions (e.g., Rho kinase inhibitors, NO donors), non-invasive approaches (e.g., laser trabeculoplasty, ultrasound, sonic therapies), and minimally invasive glaucoma surgeries. Emerging gene therapies that target TM outflow pathway show promise for long-lasting IOP control. Additionally, cell-based therapies aiming to restore TM cellularity and function represent a novel regenerative strategy. Despite significant progress, challenges remain in optimizing delivery methods, sustaining therapeutic efficacy, and ensuring safety. We highlight the evolving landscape of TM-targeted interventions and underscore the importance of continued innovation in glaucoma management.Copyright © 2025. Published by Elsevier Inc.