AMP-activated protein kinase (AMPK) is pivotal to metabolic homeostasis in eukaryotes, serving as a critical energy sensor. Increased AMPK activity during oxygen deprivation (hypoxia) protects against potentially catastrophic deficits in ATP supply. Whilst the nervous system circuitry for elaboration of the complex cardiorespiratory response to hypoxia has been understood in some detail for many decades, there is continued and considerable interest in the molecular machinery underpinning the mechanism(s) of oxygen sensing. In this issue of the Biochemical Journal, Evans et al. (2016) review their recent work, which points to a pivotal role for AMPK in the transduction of cellular hypoxic stress to integrated ventilatory behaviour, critical in the defence of whole-body oxygen homeostasis. Of great surprise, there is profound blunting of the hyperventilatory response to hypoxic stress in AMPK deficient mice, with resultant dysregulated breathing arising in spite of normal peripheral oxygen sensing and appropriate sensory input to the brain! Their pointedly provocative review challenges current dogma, and in doing so raises intriguing questions that probe fundamental aspects of our understanding of the mammalian ventilatory response to hypoxic stress. The engaging review by Evans et al. (2016) is an interesting read that is sure to encourage colourful debate.