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Background: The routine use of high inspired oxygen fractions (FiO₂) during mechanical ventilation in anesthesia and critical care is traditionally aimed at preventing hypoxemia. However, liberal oxygen administration often exceeds physiological requirements, potentially masking early signs of underlying pathology such as inadvertent endobronchial intubation, pulmonary congestion and edema, acute respiratory distress syndrome (ARDS), and other conditions associated with impaired gas exchange. This practice may delay recognition of ventilation-perfusion (V/Q) mismatch and latent hypoxemia, while also increasing the risks of oxygen toxicity and absorption atelectasis.Content: This narrative review revisits the foundational principles of Nunn’s iso-shunt diagrams as a physiological framework for understanding the interplay between FiO₂, arterial oxygenation (PaO₂), and shunt fraction. We analyze the historical development, mathematical basis, and modifications of these diagrams, highlighting their diagnostic value, especially at lower FiO₂ levels. By integrating classical physiology with contemporary monitoring and clinical evidence, we advocate for a paradigm shift away from routine hyperoxygenation toward precise, patient-specific FiO₂ titration.Conclusions: We propose that maintaining minimal FiO₂, typically less than 0.3, not only reduces hyperoxia-related harm but also unmasks subtle gas exchange impairments that remain hidden under high FiO₂ conditions. This individualized, physiologically informed approach to oxygen therapy in anesthesia promotes patient safety by earlier detection of pathological gas exchange, challenging traditional assumptions and supporting a more nuanced, evidence-based practice.