Direct bronchoprovocation challenges (eg, methacholine), which act directly on a specific airway smooth muscle receptor, are the most commonly performed challenge tests. Cut points have been arbitrarily selected to give high sensitivity and negative predictive values. In subjects with clinically current symptoms (within a few days) who inhale methacholine without deep inhalations, a normal methacholine test (provocative concentration causing a 20% fall in FEV(1) [PC(20)] > 16 mg/mL) rules out (current) asthma with reasonable certainty. A positive test in the moderate or greater range (PC(20) < 1 mg/mL) has high specificity and positive predictive value, comparable to the indirect challenges. Values between these levels are consistent with, but not diagnostic of, asthma. The positive predictive value (for clinical asthma) will increase the closer the PC(20) is to 1 mg/mL, the higher the pretest probability is for asthma and the more the methacholine-induced symptoms resemble the naturally occurring symptoms. Direct challenges are more sensitive and less specific than indirect challenges (exercise, adenosine monophosphate, mannitol, etc).