In evaluating the clinical consequences of β₂-agonist therapy, it is important to consider the possibility of reduced asthma control and increased bronchial responsiveness with regular or long-term use. Some studies have noted reductions in protective effects but not complete loss of protection with short-acting β₂-agonist therapy. These reductions vary, depending on the use of nonspecific, indirect, or immunologic challenges, but it appears there is a greater loss of protective effect against indirect stimuli. Tachyphylaxis to the bronchodilatatory effects of long-acting β₂-agonists appears to be minimal. Individuals homozygous for arginine at locus 16 of the β₂-adrenergic receptor gene have a decline in pulmonary function during β₂-agonist use, and they are at greater risk of asthma exacerbations during β₂-agonist therapy than patients with other genotypes. Important questions for further research are whether small differences in tachyphylaxis and bronchoprotection have relevant clinical effects and to what extent tachyphylaxis and tolerance to bronchoprotection are caused by pharmacogenetic interactions. (J Allergy Clin Immunol 2002;110:S304-12.)