While the principles underlying alveolar gas exchange have been well-known for over 50 years, we still struggle to assess gas exchange in hypoxemic patients. Unfortunately, simple measurements lack discrimination while complex measurements are infeasible in clinical care. The paper by Karbing et al. in this issue seeks a middle ground based on the arterial PO2 (PaO2)/inspired O2 fraction (FIO2) ratio measured at different FIO2s with the outcomes fed into proprietary software to account for both shunting and ventilation/perfusion inequality. Whether this is the optimal compromise between measurement difficulty and information available will have to be answered by those willing to test the approach in their own patients.