The article reviews the roles of Siglecs (sialic-acid-binding immunoglobulin-like lectins) in the immune system, focusing on their glycan recognition and signaling mechanisms. Siglecs are type 1 membrane proteins with an amino-terminal V-set immunoglobulin domain that binds sialic acid and variable numbers of C2-set immunoglobulin domains. They are categorized into two subsets: the V-set subset, including sialoadhesin, CD22, myelin-associated glycoprotein (MAG), and Siglec-15, and the CD33-related subset, which shows rapid evolutionary changes. The article discusses the expression patterns of Siglecs, their ligand specificity, and the role of ITIMs and ITAMs in their signaling functions. It highlights the importance of sialic acid recognition in modulating cell adhesion, signaling, and endocytosis, and explores the functions of Siglecs in immune responses, including their role in regulating B-cell activation, leukocyte behavior, and pathogen recognition. The article also examines the rapid evolution of CD33-related Siglecs and their potential roles in autoimmune diseases. Finally, it discusses the endocytic functions of Siglecs and their interactions with sialylated pathogens, emphasizing the complex interplay between Siglecs and the glycome in immune responses.The article reviews the roles of Siglecs (sialic-acid-binding immunoglobulin-like lectins) in the immune system, focusing on their glycan recognition and signaling mechanisms. Siglecs are type 1 membrane proteins with an amino-terminal V-set immunoglobulin domain that binds sialic acid and variable numbers of C2-set immunoglobulin domains. They are categorized into two subsets: the V-set subset, including sialoadhesin, CD22, myelin-associated glycoprotein (MAG), and Siglec-15, and the CD33-related subset, which shows rapid evolutionary changes. The article discusses the expression patterns of Siglecs, their ligand specificity, and the role of ITIMs and ITAMs in their signaling functions. It highlights the importance of sialic acid recognition in modulating cell adhesion, signaling, and endocytosis, and explores the functions of Siglecs in immune responses, including their role in regulating B-cell activation, leukocyte behavior, and pathogen recognition. The article also examines the rapid evolution of CD33-related Siglecs and their potential roles in autoimmune diseases. Finally, it discusses the endocytic functions of Siglecs and their interactions with sialylated pathogens, emphasizing the complex interplay between Siglecs and the glycome in immune responses.