Airway hyper-responsiveness (AHR) is a cardinal feature of asthma. Its absence has been considered useful in excluding asthma, whereas it may be present in other diseases such as atopic rhinitis and chronic obstructive pulmonary disease. AHR is often considered an epiphenomenon of airway inflammation. Actually, the response of airways to constrictor stimuli is modulated by a complex array of factors, some facilitating and others opposing airway narrowing. Thus, it has been suggested that AHR, and perhaps asthma, might be present even without or before the development of airway inflammation. We begin this review by highlighting some terminological and methodological issues concerning the measurement of AHR. Then we describe the neurohumoral mechanisms controlling airway tone. Finally, the pivotal role of airway smooth muscle and internal and external modulation of airway caliber in vivo are discussed in detail.