As air is breathed in, it follows a complex pathway of branching airways on its way to the alveolar spaces of the lung. Two basic regions of ventilation are recognized, one that participates in gas exchange, the alveolar ventilation, and one that serves as the conduit for air to reach the gas exchange region, the dead space ventilation. Ventilation is not evenly distributed throughout the lung. First, because of the weight of the lung, the more dependent regions of the lung are more compliant and therefore receive more ventilation than less dependent regions. Secondly, topographic ventilation heterogeneity also exists because of the varying time constants (resistance x compliance) scattered throughout the lung, resulting in fast and slow filling and emptying of different regions. This unevenness of ventilation can be detected by a variety of methods, but inert gas washout techniques, including single and multiple-breath nitrogen washout, are most common. This chapter will explore in more detail the physiology of ventilation heterogeneity, how it is measured, and what its implications may be for clinical medicine.