Two very large, randomized, double-blind clinical trials performed in the United Kingdom and in the United States have suggested that addition of salmeteräE to usual asthma therapy is associated with a significant increase in the incidence of serious adverse events and asthma-related deaths compared with addition of albuterol or placebo to usual therapy in the same type of patients. These results prompted the United States Food and Drug Administration (FDA) to issue a stern warning regarding these potential adverse effects and to advise that long-acting beta-agonists (LABAs) should not used as first-line therapy for the treatment of asthma. Two potential explanations have been proposed for these unexpected adverse effects. It has been suggested that more than a direct pharmacological effect of LABAs, these adverse events result from inadequate concomitant use of inhaled corticosteroids in subjects treated with these medicines. However, a detailed analysis of the results of the two large trials did not provide definitive conclusions regarding the potential protective role of inhaled corticosteroids. A second explanation, which the author here considers more plausible, is that a small group of patients with asthma develop idiosyncratic responses to LABAs, and common or rare variants in the genes that encode for proteins associated with the pharmacological response to these medicines are strongly suspected to predispose for these unusual deleterious responses. Until the biological mechanisms involved are better understood, efforts should be made to confine the use of LABAs to those patients who really need them.