Oxygen occupies a key role in cellular metabolism and function. Oxygen delivery to cells is crucial and a lack of oxygen such as occurs during myocardial infarction can be lethal. Cells must therefore be able to respond to changes in oxygen tension. Since the first studies examining the acute cellular effect of hypoxia on activation of transmitter release from glomus or type I chemoreceptor cells, it is now known that virtually all cells are able to respond to changes in oxygen tension. Despite advances made in characterising hypoxic responses, the identity of the oxygen sensor remains debated. Recently, more evidence has evolved as to how cardiac myocytes sense acute changes in oxygen. This review will examine the available evidence in support of acute oxygen sensing mechanisms with special reference to the heart. Further understanding these cellular processes should lead to interventions that assist in preventing the deleterious effects of acute changes in oxygen tension such as alterations in contractile function and cardiac arrhythmia.