The diagnosis of respiratory failure is based on the partial pressures of oxygen in the arterial blood (PaO2). A large number of conditions are capable of manifesting this serious condition. Classification into Type-1 (hypoxemic) and Type-2 (hypercapnic) respiratory failure not only has a strong physiologic basis but enables pruning of the differential diagnosis into a manageable list of conditions and evolving a strategy for directed workup. This chapter explores the physiology of oxygenation, the relationship between the partial pressures of oxygen in the various compartments of the lung and vasculature, the indices of oxygenation and proposes a systemic approach directed at uncovering the specific causes of both types of respiratory failures. It also suggests a unique approach for uncovering a combination of conditions that may be responsible for respiratory failure.