The receptor for advanced glycation end-products (RAGE) has emerged as a crucial player in various human diseases, including diabetes, cardiovascular diseases, neurodegenerative disorders, autoimmune diseases, chronic airways diseases, and cancer. Initially identified for its role in diabetes complications, RAGE's functions have expanded to include interactions with a wide range of structurally diverse ligands, making it a pattern recognition receptor (PRR). The binding of these ligands to RAGE triggers a complex signaling cascade, leading to cellular dysfunction and inflammatory responses. This review summarizes the basic features of the RAGE axis biology and its contributions to several human diseases. Key aspects discussed include the human *AGER* gene, protein structure, ligand repertoire, expression and distribution, signaling pathways, and therapeutic and diagnostic potential. The RAGE axis is highlighted as a relevant inflammatory hub that can be targeted for therapeutic intervention, but its role in normal physiology requires further research to fully understand its clinical relevance.The receptor for advanced glycation end-products (RAGE) has emerged as a crucial player in various human diseases, including diabetes, cardiovascular diseases, neurodegenerative disorders, autoimmune diseases, chronic airways diseases, and cancer. Initially identified for its role in diabetes complications, RAGE's functions have expanded to include interactions with a wide range of structurally diverse ligands, making it a pattern recognition receptor (PRR). The binding of these ligands to RAGE triggers a complex signaling cascade, leading to cellular dysfunction and inflammatory responses. This review summarizes the basic features of the RAGE axis biology and its contributions to several human diseases. Key aspects discussed include the human *AGER* gene, protein structure, ligand repertoire, expression and distribution, signaling pathways, and therapeutic and diagnostic potential. The RAGE axis is highlighted as a relevant inflammatory hub that can be targeted for therapeutic intervention, but its role in normal physiology requires further research to fully understand its clinical relevance.