© Copyright 2015, Mary Ann Liebert, Inc. 2015. Significance: Oxygen plays a key role in cellular metabolism and function. Oxygen delivery to cells is crucial, and a lack of oxygen such as that which occurs during myocardial infarction can be lethal. Cells should, therefore, be able to respond to changes in oxygen tension. Recent Advances: 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. Critical Issues: Despite advances made in characterizing 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 providing a brief historical perspective and then more detailed insights into the heart and the role of cardiac ion channels in hypoxic responses. Future Directions: A further understanding of these cellular processes should result in interventions that assist in preventing the deleterious effects of acute changes in oxygen tension such as alterations in contractile function and cardiac arrhythmia. Antioxid. Redox Signal. 22, 522-536.