© 2016 by The American Association of Immunologists, Inc. All rights reserved. Glycans constitute basic cellular components of living organisms across biological kingdoms, and glycanbinding Abs participate in many cellular interactions during immune defense against pathogenic organisms. Glycan epitopes are expressed as carbohydrate-only entities or as oligomers or polymers on proteins and lipids. Such epitopes on glycoproteins may be formed by posttranslational modifications or neoepitopes resulting from metabolic-catabolic processes and can be altered during inflammation. Pathogenic organisms can display host-like glycans to evade the host immune response. However, Abs to glycans, shared between microorganisms and the host, exist naturally. These Abs are able to not only protect against infectious disease, but also are involved in host housekeeping functions and can suppress allergic disease. Despite the reactivity of these Abs to glycans shared between microorganisms and host, diverse tolerance-inducing mechanisms permit the B cell precursors of these Ab-secreting cells to exist within the normal B cell repertoire.