The world is facing an explosive COVID-19 pandemic. Some cases rapidly develop deteriorating lung function, which causes deep hypoxaemia and requires urgent treatment. Many centres have started treating patients in the prone position, and oxygenation has improved considerably in some cases. Questions have been raised regarding the mechanisms behind this. The mini review provides some insights into the role of supine and prone body positions and summarises the latest understanding of the responsible mechanisms. The scope for discussion is outside the neonatal period and entirely based on experimental and clinical experiences related to adults. The human respiratory system is a complex interplay of many different variables. Therefore, this mini review has prioritised previous and ongoing research to find explanations based on three scientific areas: gravity, lung structure and fractal geometry and vascular regulation. It concludes that gravity is one of the variables responsible for ventilation/perfusion matching but in concert with lung structure and fractal geometry, ventilation and regulation of lung vascular tone. Since ventilation distribution does not change between supine and prone positions, the higher expression of nitric oxide in dorsal lung vessels than in ventral vessels is likely to be the most important mechanism behind enhanced oxygenation in the prone position.