In the mammalian cardiovascular system, endothelial glycocalyx is a gel-like layer that covers the luminal surface of endothelial cells (ECs) and plays crucial roles in vascular homeostasis, permeability and leukocyte adhesion. Degradation of this structure occurs early in sepsis and becomes accordingly dysfunctional. In severe cases, it is not self-regulated by the organism. However, the relationship between the glycocalyx and the occurrence and development of sepsis remains poorly understood. One possibility is that thinned glycocalyx promotes leukocyte recognition and adhesion, thereby facilitating the elimination of pathogens from infected areas. This may represent a protective mechanism developed by the organism during through evolutionary processes. However, if the damage persists and disrupts the dynamic balance of the microcirculation, interstitial edema or organ failure can occur. Thus, we asked the questions, what is the precise composition and structure of the glycocalyx? How is it degraded? What animal models are available to study the relationship between the glycocalyx and sepsis? What glycocalyx biomarkers are found in the blood of patients with sepsis? To determine whether sepsis can be treated by interfering with the glycocalyx, this study provides a systematic summary and discussion of the latest progress in addressing these questions.