Non-uniform distribution of inspired gas within the lung, termed ventilation heterogeneity, is present in patients with even mild asthma. Current evidence strongly supports ventilation heterogeneity as a fundamental derangement of lung function in asthma that contributes per se to hypoxemia and airway hyper-responsiveness. An extreme example of ventilation heterogeneity is the identification by hyperpolarized gas MRI of lung regions with no ventilation, termed filling defects. Lung filling defects in patients with asthma can persist over time, increase in size with methacholine-induced bronchospasm and more likely are caused by obstruction of the peripheral and not the proximal airways. Ventilation heterogeneity can be quantified in the conducting and acinar lung zones with the multiple gas washout method, and in the acinar zone does not fully resolve following bronchodilator treatment in patients with asthma. In prospective studies, the degree of ventilation heterogeneity at baseline predicts airway hyper-responsiveness and response to corticosteroid dose titration. An important unanswered question is the relationship of airways inflammation to ventilation heterogeneity. In consideration of the importance of ventilation heterogeneity in its pathobiology, asthma is more a focal disorder with regional pathology akin to regional ileitis and not the generalized disorder of the airways as it has been viewed in the past.