Regional tissue distress caused by microcirculatory dysfunction and mitochondrial depression underlies the condition in sepsis and shock where, despite correction of systemic oxygen delivery variables, regional hypoxia and oxygen extraction deficit persist. We have termed this condition microcirculatory and mitochondrial distress syndrome (MMDS). Orthogonal polarization spectral imaging allowed the first clinical observation of the microcirculation in human internal organs, and has identified the pivotal role of microcirculatory abnormalities in defining the severity of sepsis, a condition not revealed by systemic hemodynamic or oxygen-derived variables. Recently, sublingual sidestream dark-field (SDF) imaging has been introduced, allowing observation of the microcirculation in even greater detail. Microcirculatory recruitment is needed to ensure adequate microcirculatory perfusion and the oxygenation of tissue cells that follows. In sepsis, where inflammation-induced autoregulatory dysfunction persists and oxygen need is not matched by supply, the microcirculation can be recruited by reducing pathological shunting, promoting microcirculatory perfusion, supporting pump function, and controlling hemorheology and coagulation. Resuscitation following MMDS must include focused recruitment of hypoxic-shunted microcirculatory units and/or resuscitation of the mitochondria. A combination of agents is required for successful rescue of the microcirculation. Single compounds such as activated protein C, which acts on multiple pathways, can be expected to be beneficial in rescuing the microcirculation in sepsis.