Building solid evidence in intensive care medicine is challenging, mostly due to patient heterogeneity and concomitant treatment interactions. In the context of acute respiratory distress syndrome (ARDS), only two interventions have demonstrated a positive impact on patient survival with high quality of evidence. The first is a low-tidal volume, low-plateau pressure ventilation [1], and the second is prone positioning (PP) of patients with moderate-to-severe hypoxemia [2]. The latter recommendation was achieved after a long journey marked by trials that failed for various reasons, including insufficient sample size, [3] relatively short duration of the PP cycles, [4, 5] patient selection criteria [4,5,6], and inadequate ventilation strategy. Guerin et al. [2] discovered the “optimal formula” for PP, emphasizing its early application combined with low-tidal volume ventilation, muscle relaxants, and prolonged sessions lasting at least 16 h. Most importantly, they implemented PP only in patients with more severe hypoxemia, defined as PaO₂ to FiO₂ ratio below 150 mmHg after a stabilization period with standardized ventilation settings. The most hypoxemic patients usually present a smaller end-expiratory lung volume (“baby lung”) due to a higher amount of collapse in the dependent lung regions [7]. Prone positioning is associated with a redistribution and homogenization of ventilation from ventral to dorsal lung regions, thus mitigating the risk of overdistension of nondependent zones and facilitating the reopening of poorly aerated or collapsed dependent regions. These changes result in a reduction of intrapulmonary shunt fraction and in a better matching of ventilation and perfusion, which in turn translates into an improvement of oxygenation.