Heterogeneity is a feature of both normal oxygen supply to tissue and of a supply that is disturbed due to a wide range of different pathologies. Here, the physiological importance of heterogeneity of tissue oxygenation is revisited. The anatomical and functional basis for heterogeneity of blood flow, local and regional regulatory mechanisms in normal tissues and the pathophysiology of the failure of regulation will be examined.Under physiological conditions, regulation of blood flow distributions at global, regional and microregional levels play coordinated roles in ensuring adequate O2 supply to all tissue cells. How this is achieved may be organ-/organ layer-specific, depending on its function and priorities to match local O2 delivery to consumption. Examples where these regulatory mechanisms break down under conditions of ischaemia and shock will also be given.In contrast, pathologic heterogeneity in tissue oxygenation resulting from uncontrolled, chaotic growth as seen in malignant tumours represents a pathophysiological status that is not predictable which, in general, is associated with chronic and acute hypoxia. This can have fatal consequences due to hypoxia- induced (mal-)adaptive processes, malignant tumour progression and treatment resistance.