Aerobic cellular respiration depends on the efficient supply of oxygen and substrate to the mitochondria. There is an oxygen cascade from the environment to the subcellular environment. Efficient oxygen delivery depends on the coordinated interaction between the respiratory and circulatory systems. The circulation at both macro- and microvascular levels is under the control of humoral and neural factors. There is local autoregulation of flow at the tissue level by metabolic factors which reflect the energy state of the tissues. The response to hypoxia involves the activation of cytokines and genetically controlled factors which maximise capillary perfusion and haemoglobin concentration, and regulate cell metabolism. The formation of reactive oxygen species under such conditions has a detrimental effect on the mitochondria with respiratory chain dysfunction, increased permeability transition, and cell death. This review aims to explore the mechanisms by which the body attempts to maintain tissue oxygen levels at conditions optimal for cell survival.