Sialic acids are one of the important constituents of glycoconjugates in the deuterostome lineage of animals and microorganisms. Siglecs (Sialic acid-binding immunoglobulin like lectins) are a family of cell-surface receptor proteins that recognize sialylated glycoconjugates as ligands. To date, 15 Siglecs have been described in humans and are mainly known as regulators of the immune system. Several of the Siglecs are emerging as potential targets for the treatment of some inflammatory, autoimmune, allergic, neurodegenerative and infectious diseases. In addition to antibody mediated therapy, high-affinity ligand-based probes of Siglec receptors would represent invaluable tools to effectively address therapeutic opportunities of Sialic acid-mediated Siglec recognition. This review discusses some aspects of structure and function of Siglec receptors, and concisely summarizes up-to-date progress on the identification of sialic acid based high-affinity ligands of certain well explored Siglec receptors.