The 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 can become harmful if overactive and/or dysregulated. Pathologic microcirculatory dysfunction can be directly visualized by intravital microscopy or indirectly measured via detection of circulating biomarkers. Although several treatments have been shown to protect the microcirculation during sepsis, they have not improved patient outcomes when applied indiscriminately. Future outcomes-oriented studies are needed to test sepsis therapeutics when personalized to a patient’s microcirculatory dysfunction.