The principal function of the lung is to facilitate the exchange of the respiratory gases, oxygen (O2) and carbon dioxide (CO2). When the lung fails as a gas exchanger respiratory failure ensues. Clinically, it is generally accepted that an arterial oxygen tension (PaO2) of less than 60 mmHg or a PaCO2 of greater than 50 mmHg, or both, whilst breathing room air are values consistent with the concept of respiratory failure. This article will deal, firstly, with some basic aspects of the physiology of pulmonary gas exchange and more specifically on the measurement of ventilation-perfusion (VA/Q) relationships, the most influential factor determining hypoxaemia. The second part highlights the most important findings on pulmonary gas exchange in the adult respiratory distress syndrome (ARDS) and other common acute respiratory failure conditions, such as pneumonia, acute exacerbation of chronic obstructive pulmonary disease (COPD) and status asthmaticus, based on the data obtained by means of the multiple inert gas elimination approach, a technique which gives a detailed picture of VA/Q ratio distributions.