A series of investigations show that the regular use of inhaled β₂ -agonists will increase all aspects of the airway response to allergen. The mechanism of this effect is uncertain; however, it appears to be different from the mechanism that produces tolerance to β₂ -agonist effects. One possibility is that the regular use of β₂ -agonists might induce a mast cell β-receptor dysfunction that might make mast cells more prone to release mediators. As a result β₂ -agonist use plus allergen exposure might cause more mediator release than does allergen exposure alone. The corollary of this is that β₂ -agonist use plus allergen exposure might cause more airway inflammation than does allergen exposure alone. These hypotheses are both testable. I believe that this is a clinically important phenomenon and may well be a major reason for β₂ -agonist–induced worsened asthma control. Further investigations are indicated to identify the mechanism and the clinical relevance of the phenomenon. (J Allergy Clin Immunol 1998;102:S96-9)