Siglecs are a family of sialic-acid-binding immunoglobulin-like lectins that play important roles in the immune system by recognizing glycans and regulating cell-cell interactions and signaling. They are type 1 membrane proteins with an amino-terminal V-set immunoglobulin domain that binds sialic acid and multiple C2-set immunoglobulin domains. Siglecs are divided into two subsets based on sequence similarity and evolutionary conservation. CD33-related Siglecs show rapid evolution, likely due to their need to keep up with the changing sialome of the host, and have diverse expression patterns in the innate immune system. Some Siglecs, such as CD22, have inhibitory functions through ITIMs, while others, like Siglec-H and Siglec-14, lack ITIMs and instead interact with DAP12. Siglecs recognize various sialylated glycans, with CD22 showing a strong preference for Neu5Ac α2-6Gal and Neu5Gc α2-6Gal. The binding of Siglecs to sialylated glycans is influenced by the type of sialic acid, its linkage, and the structure of the underlying glycan. Siglecs can mediate both cell-cell interactions and signaling functions, and their precise roles and relevant ligands are still being studied. Recent studies using genetically manipulated mice have begun to shed light on the complex factors involved in Siglec function. CD33-related Siglecs have undergone significant changes during human evolution, and their roles in immune regulation are being further elucidated. Siglecs can also function as endocytic receptors, which may be important in the clearance of sialylated antigens and in antigen presentation. Their signaling pathways are poorly understood but are assumed to involve ITIM and ITIM-like motifs and the recruitment of tyrosine phosphatases. CD33-related Siglecs have been shown to regulate cell growth and survival, either by inhibiting proliferation or inducing apoptosis. They also play a role in modulating leukocyte behavior, including inhibition of cellular proliferation, induction of apoptosis, and suppression of interferon-α production. The study of Siglecs has provided important insights into their roles in immune regulation and their potential as therapeutic targets.Siglecs are a family of sialic-acid-binding immunoglobulin-like lectins that play important roles in the immune system by recognizing glycans and regulating cell-cell interactions and signaling. They are type 1 membrane proteins with an amino-terminal V-set immunoglobulin domain that binds sialic acid and multiple C2-set immunoglobulin domains. Siglecs are divided into two subsets based on sequence similarity and evolutionary conservation. CD33-related Siglecs show rapid evolution, likely due to their need to keep up with the changing sialome of the host, and have diverse expression patterns in the innate immune system. Some Siglecs, such as CD22, have inhibitory functions through ITIMs, while others, like Siglec-H and Siglec-14, lack ITIMs and instead interact with DAP12. Siglecs recognize various sialylated glycans, with CD22 showing a strong preference for Neu5Ac α2-6Gal and Neu5Gc α2-6Gal. The binding of Siglecs to sialylated glycans is influenced by the type of sialic acid, its linkage, and the structure of the underlying glycan. Siglecs can mediate both cell-cell interactions and signaling functions, and their precise roles and relevant ligands are still being studied. Recent studies using genetically manipulated mice have begun to shed light on the complex factors involved in Siglec function. CD33-related Siglecs have undergone significant changes during human evolution, and their roles in immune regulation are being further elucidated. Siglecs can also function as endocytic receptors, which may be important in the clearance of sialylated antigens and in antigen presentation. Their signaling pathways are poorly understood but are assumed to involve ITIM and ITIM-like motifs and the recruitment of tyrosine phosphatases. CD33-related Siglecs have been shown to regulate cell growth and survival, either by inhibiting proliferation or inducing apoptosis. They also play a role in modulating leukocyte behavior, including inhibition of cellular proliferation, induction of apoptosis, and suppression of interferon-α production. The study of Siglecs has provided important insights into their roles in immune regulation and their potential as therapeutic targets.