Airway hyperresponsiveness (AHR) is a characteristic feature of asthma, and histamine and methacholine bronchoprovocation challenges have been widely used to document and quantitate AHR.1 In 1987, Pauwels et al2 proposed that stimuli used in bronchoprovocation could be divided into direct and indirect. The direct stimuli act directly on a specific airway smooth muscle receptor and include muscarinic agonists (ie, methacholine), histamine, leukotrienes, and prostaglandins. The indirect stimuli act through one or more intermediate pathways, many (but not all) of which involve release of mediators from inflammatory cells, primarily metachromatic cells. Mediator-releasing indirect stimuli include exercise, eucapnic voluntary hyperpnea, hypertonic saline, adenosine monophosphate (AMP), and mannitol. Indirect stimuli acting through other mechanisms include propranolol, tachykinins, and bradykinin, but these will not be further discussed in this article. Because the naturally occurring stimuli causing symptoms in asthma act through indirect mechanisms, Pauwels et al2 hypothesized that indirect airway responsiveness should correlate better with clinical features of asthma, including severity and control, current asthma activity, and so forth.