Oxygen is needed to generate aerobic adenosine triphosphate and energy that is required to support vital cellular functions. Oxygen delivery (DO₂) to the tissues is determined by convective and diffusive processes. The ability of the body to adjust oxygen extraction (ERO₂) in response to changes in DO₂ is crucial to maintain constant tissue oxygen consumption (VO₂). The capability to increase ERO₂ is the result of the regulation of the circulation and the effects of the simultaneous activation of both central and local factors. The endothelium plays a crucial role in matching tissue oxygen supply to demand in situations of acute drop in tissue oxygenation. Tissue oxygenation is adequate when tissue oxygen demand is met. When DO₂ is severely compromised, a critical DO₂ value is reached below which VO₂ falls and becomes dependent on DO₂, resulting in tissue hypoxia. The different mechanisms of tissue hypoxia are circulatory, anaemic, and hypoxic, characterised by a diminished DO₂ but preserved capacity of increasing ERO₂. Cytopathic hypoxia is another mechanism of tissue hypoxia that is due to impairment in mitochondrial respiration that can be observed in septic conditions with normal overall DO₂. Sepsis induces microcirculatory alterations with decreased functional capillary density, increased number of stopped-flow capillaries, and marked heterogeneity between the areas with large intercapillary distance, resulting in impairment of the tissue to extract oxygen and to satisfy the increased tissue oxygen demand, leading to the development of tissue hypoxia. Different therapeutic approaches exist to increase DO₂ and improve microcirculation, such as fluid therapy, transfusion, vasopressors, inotropes, and vasodilators. However, the effects of these agents on microcirculation are quite variable.