Siglecs are sialic acid-binding immunoglobulin-like lectins. Most Siglecs function as transmembrane receptors mainly expressed on blood cells in a cell type-specific manner. They recognize and bind sialic acids in specific linkages on glycoproteins and glycolipids. Since Sia is a self-molecule, Siglecs play a role in innate immune responses by distinguishing molecules as self or non-self. Increasing evidence supports the involvement of Siglecs in immune signaling representing immune checkpoints able to regulate immune responses in inflammatory diseases as well as cancer. Although further studies are necessary to fully understand the involvement of Siglecs in pathological conditions as well as their interactions with other immune regulators, the development of therapeutic approaches that exploit these molecules represents a tremendous opportunity for future treatments of several human diseases, as demonstrated by their application in several clinical trials. In the present review, we discuss the involvement of Siglecs in the regulation of immune responses, with particular focus on autoimmunity and cancer and the chance to target the sialic acid-Siglec axis as novel treatment strategy.