Vascular endothelial cells (ECs) form a barrier that plays a crucial role in the health and integrity of tissues by regulating the passage of molecules, liquids and immune cells. Dysfunctions or disruption of this barrier lead to edema, inflammation, and associated pathologies. During infection, ECs control transmigration of cells by a complex system of molecules. However pathogens can hijack this pathway to invade ECs and/or tissues. They can also trigger the opening of intercellular junction, apoptosis of ECs or activation of the immune system, which in turn lead to the destruction of the endothelial wall and subsequent edema. Activation of immune cells by pathogens can also enhance the destruction of EC and edema. The review summarizes the state-of-the-art knowledge on the key steps of the complex interactions between the endothelial wall, pathogens, and the immune system that lead to the opening of junctions and/or destruction of the wall, enhancing pathology. A better understanding of these points will allow the development of adjunctive treatments to be used in combination with therapies targeting pathogens, with the aim of protecting the wall and improving the recovery of patients with severe infectious diseases.