N-glycolneuraminic acid (Neu5Gc) is a sialic acid mainly found in mammalian species. It is absent in humans. This is due to an irreversible mutation of the CMP-Neu5Ac hydroxylase (CMAH) enzyme in humans, rendering them unable to synthesize Neu5Gc. The human body identifies Neu5Gc as “foreign”; and anti-Neu5Gc antibodies are produced by the human body in response to any metabolically incorporated, diet-derived Neu5Gc, as found in ingested red meats and dairy products.Varying quantities of Neu5Gc is found in some approved biotherapeutics used for the treatment of numerous medical conditions. This leads to the debate of potential risks and/or benefits of Neu5Gc in humans. The effects of the interaction between anti-Neu5Gc antibodies and antigenic Neu5Gc-containing biotherapeutics in humans are largely unknown and there are many discrepancies in terms of scientific evidence. This article reviews and discusses the current knowledge in the understanding of Neu5Gc in the human body and its potential significance.