Sialic acids are a family of acidic sugars with a 9-carbon backbone, prominently expressed in animals of deuterostome lineage. Siglecs are the largest family of vertebrate endogenous receptors that recognize glycoconjugates containing sialic acids. Although a few Siglecs are well-conserved throughout vertebrate evolution and show similar binding preference regardless of the species of origin, most others, particularly the CD33-related subfamily of Siglecs, show marked inter-species differences in repertoire, sequence, and binding preference. The diversification of CD33-related Siglecs may be driven by direct competition against pathogens, and/or by necessity to catch up with the changing landscape of endogenous glycans, which may in turn be changing to escape exploitation by other pathogens.