Sialic acid (Sia) is widely distributed in free, polymeric and conjugated forms in living creatures and humans. It serves various roles in human physiology including brain development, function of central nervous system, the immune system, lactation and infant cognition. Sia is over- or under-expressed in human cells, tissues and fluids during physiological disorders and the onset of cancers. Furthermore, the exploitation of Sia by several bacteria and viruses including SARS-CoV-2 to cause human infections has been recently revealed. A special chemical form of Sia and 3′- and 6′-sialyllactose have recently received regulatory approval for use in commercial food products as nutrition additives. Therefore, Sia production and assay have immense clinical and industrial interests. However, sensing or analytical approaches to Sia measurement in complex clinical and food samples are less developed due to lack of a comprehensive review covering both fundamental and perspectives to general readers working at the periphery of Sia. This review provides a carefully balanced and comprehensive collation of key aspects of the monosaccharide family of Sia, covering their sources, synthesis, biological significance, role in disease and human health and nutrition, culminating in a robust account of their analysis in complex matrices.