<p>The glycocalyx is a fuzzy structure covering the luminal surface of vascular endothelial cells. Its name was first proposed by Bennett, derived from the Latin word meaning ‘sweet shell’. This was confirmed by Luft in 1966 through ruthenium red staining under electron microscopy. In recent years, the role of the glycocalyx in the pathophysiological processes of various diseases, such as cardiovascular diseases, chronic kidney disease, sepsis, COVID-19 infection, and diabetes, has gradually attracted widespread attention, and its importance has been increasingly recognized. In these acute and chronic clinical situations, the endothelium surface may lose syndecans, heparan sulfate (HS), and hyaluronan (HA), the primary constituents of the glycocalyx, a process involving multiple degrading enzymes. This review aims to start from the mechanisms of glycocalyx degradation, systematically elaborate on the factors related to degradation, enzymes involved in the degradation process, and signaling pathways. It also explores pharmacological drugs with the potential to reduce glycocalyx shedding, as found in current laboratory and clinical studies. In this review, it is expected to provide a reference for a deeper understanding of the role of glycocalyx in physiological and pathological processes and to offer new ideas and targets for the development of diagnostic, therapeutic, and preventive strategies for related diseases.</p> Graphical Abstract <p></p>