Endothelial cells (ECs) are vascular, nonconventional immune cells that play a major role in the systemic response after bacterial infection to limit its dissemination. Triggered by exposure to pathogens, microbial toxins, or endogenous danger signals, EC responses are polymorphous, heterogeneous, and multifaceted. During sepsis, ECs shift toward a proapoptotic, proinflammatory, proadhesive, and procoagulant phenotype. In addition, glycocalyx damage and vascular tone dysfunction impair microcirculatory blood flow, leading to organ injury and, potentially, life-threatening organ failure. This review aims to cover the current understanding of the EC adaptive or maladaptive response to acute inflammation or bacterial infection based on compelling recent basic research and therapeutic clinical trials targeting microvascular and endothelial alterations during septic shock.