AbstractOver the past decade, following the discovery of the human heme protein neuroglobin, many studies have searched for evidence for this protein's mechanism of action. Much data has accrued showing that high levels of neuroglobin will protect cells from apoptotic cell death, following a wide range of challenges. Various explanations of its actions, based on measured reactivity with oxygen, nitric oxide, or free radicals, have been proposed, but none have, as yet, been substantiated in vivo. Following preliminary experiments, it was previously hypothesised that “the central role of neuroglobin in highly metabolically active cells and retinal and brain neurons is to reset the trigger level of mitochondrial cytochrome c release necessary to commit the cells to apoptosis” (I.U.M.B.M. Life (2008) 60, 398). In this article, we review the evidence, which has accumulated to support this hypothesised mechanism of action of neuroglobin and integrate this data, with other reported intracellular functions of neuroglobin, to suggest a plausible central role for neuroglobin in the control of apoptosis. © IUBMB IUBMB Life, 62(12): 878–885, 2010.