AGER encodes a cell surface pattern recognition receptor that binds advanced glycation end products (AGEs), S100 proteins, HMGB1, amyloid-beta, nucleic acids, histones, and other endogenous stress signals. Upon ligand binding, AGER transduces pro-inflammatory signals through MyD88 and TIRAP adapters, activating NF-κB and triggering production of IL-6, IL-8, and TNF-α. Beyond inflammation, AGER facilitates amyloid-beta cellular uptake in neurons, promotes endothelial hyperpermeability via RAGE/SRC/Caveolin-1 signaling, enhances HMGB1-mediated hepatocyte pyroptosis through NLRP3 inflammasome activation, and mediates DNA damage repair at double-strand breaks by stabilizing the MRN complex. AGER also promotes phagocytosis of pathogens and apoptotic cells and protects replication fork stability during DNA replication stress. AGER dysfunction associates with multiple diseases through both ligand accumulation and genetic variation. AGEs accumulate at accelerated rates in diabetes and aging, promoting vascular complications, neurodegeneration, and cancer. Recent evidence suggests oxidized IL-33 activates an alternative AGER/EGFR pathway independent of ST2, driving airway epithelial remodeling in chr6 obstructive pulmonary disease 1. In hepatocellular carcinoma in type 2 diabetes, AGE-mediated changes in collagen mechanics enhance extracellular matrix viscoelasticity, promoting HCC progression through integrin-β1-tensin-1-YAP mechanotransduction, while AGER1-mediated AGE clearance reduces growth 2. AGER polymorphisms, including rs2070600, rs1800624, rs1800625, and rs184003, associate with variable disease susceptibility across ethnic populations, influencing risk for autoimmune diseases, diabetes complications, cancer, and cardiovascular disease 3. Cyclophilin A represents a previously unrecognized AGER ligand driving thrombo-inflammatory responses 4. Protective variants suggest potential for AGE-targeting or AGER modulation in therapeutic development.