SYNOPSISThe microcirculation is a series of arterioles, capillaries, and venules that performs essential functions of oxygen and nutrient delivery, customized to the unique physiologic needs of the supplied organ. The homeostatic microcirculatory response to infection, which includes barrier hyperpermeability, leukocyte adhesion, and coagulation activation, can become harmful if overactive and/or dysregulated, contributing to the organ failure characteristic of sepsis. In humans, pathologic microcirculatory dysfunction can be directly visualized by intravital microscopy or indirectly measured via detection of circulating biomarkers, such as endothelial glycocalyx fragments. While several treatments have been shown to protect the microcirculation during sepsis, these therapies have not improved patient outcomes when applied indiscriminately. Future outcomes-oriented studies are needed to test the utility of sepsis therapeutics when applied in a manner "personalized" to a patient's microcirculatory dysfunction.