All mammalian cells display a diverse array of glycan structures that differ from those that are found on microbial pathogens. Siglecs are a family of sialic acid-binding immunoglobulin-like receptors that participate in the discrimination between self and non-self, and that regulate the function of cells in the innate and adaptive immune systems through the recognition of their glycan ligands. In this Review, we describe the recent advances in our understanding of the roles of Siglecs in the regulation of immune cell function in infectious diseases, inflammation, neurodegeneration, autoimmune diseases and cancer.