One mystery of COVID-19 is the occurrence of silent hypoxaemia, a condition where some patients experience dangerously low levels of oxygen in the blood without apparent awareness or discomfort (often misleadingly termed “happy hypoxia”). In a recent Editor’s Choice 2021 Review in The Journal of Physiology, Center Director Gordon Mitchell and an international team of experts in control of breathing and respiratory sensation discuss physiological principles that help explain this phenomenon and its implications for research and treatment for COVID-19.