The endothelium is lined by a protective mesh of proteins and carbohydrates called the endothelial glycocalyx (EG). This layer creates a negatively charged gel-like barrier between the vascular environment and the surface of the endothelial cell. When intact the EG serves multiple functions, including mechanotransduction, cell signaling, regulation of permeability and fluid exchange across the microvasculature, and management of cell-cell interactions. In trauma and/or hemorrhagic shock, the glycocalyx is broken down, resulting in the shedding of its individual components. The shedding of the EG is associated with increased systemic inflammation, microvascular permeability, and flow-induced vasodilation, leading to further physiologic derangements. Animal and human studies have shown that the greater the severity of the injury, the greater the degree of shedding, which is associated with poor patient outcomes. Additional studies have shown that prioritizing certain resuscitation fluids, such as plasma, cryoprecipitate, and whole blood over crystalloid shows improved outcomes in hemorrhaging patients, potentially through a decrease in EG shedding impacting downstream signaling. The purpose of the following paragraphs is to briefly describe the EG, review the impact of EG shedding and hemorrhagic shock, and begin entertaining the notion of directed resuscitation. Directed resuscitation emphasizes transitioning from macroscopic 1:1 resuscitation to efforts that focus on minimizing EG shedding and maximizing its reconstitution.