The structure of a sialoglycan can be translated into to a biological response when it binds to a specific endogenous lectin. Among endogenous sialic acid-binding lectins in humans are those comprising the 15-member Siglec family, most of which are expressed on overlapping sets of immune cells. Endogenous Siglec ligands are sialoglycolipids (gangliosides) and/or sialoglycoproteins, on cell surfaces or in the extracellular milieu, that bind to and initiate signaling by cell surface Siglecs. In the nervous system, where gangliosides are the predominant sialoglycans, Siglec-4 (myelin-associated glycoprotein) on myelinating cells binds to gangliosides GD1a and GT1b on nerve cell axons to ensure stable and productive axon-myelin interactions. In the immune system, Siglec-7 on natural killer cells binds to gangliosides GD3 and GD2 to inhibit immune signaling. Expression of GD3 and GD2 on cancer cells can lead to tumor immune evasion. Siglec-1 (sialoadhesin, CD169) on macrophages binds to gangliosides on tumors and enveloped viruses. This may enhance antigen presentation in some cases, or increase viral distribution in others. Several other Siglecs bind to gangliosides in vitro, the biological significance of which has yet to be fully established. Gangliosides, which are found on all human cells and tissues in cell-specific distributions, are functional Siglec ligands with varied roles driving Siglec-mediated signaling.