The apparent paradoxical data emanating from controlled laboratory challenges and long-term effects on clinical responses with or without concomitant glucocorticosteroids poses a dilemma for the primary care health professional. This is compounded by the fact that these studies are often based on variable experimental designs that may not have predetermined statistical power. In an attempt to resolve this controversy, Prieto et al (see page 798 in this issue of CHEST) performed a 6-week, controlled (placebo vs salmeterol) study that utilized a well-defined allergic phenotype of mild asthma (ie, pollen sensitive asthmatics), a well-defined exposure period (ie, a grass pollen season), direct and indirect measures of AHR (ie, methacholine and AMP), and ENO as a marker of airway inflammation.25 Airway caliber (FEV1), AHR indexes (methacholine, AMP) and ENO were measured before the administration of salmeterol or placebo and at midseason. Concurrent glucocorticosteroids were not permitted to avoid the confounding effects of these agents. As expected, patients receiving salmeterol experienced significant protection against a fall in FEV1 during the height of the allergy season, as compared to placebo. Under natural allergen exposure conditions, a significant increase in methacholine-induced AHR was observed only in the placebo group, while patients receiving salmeterol exhibited a small, insignificant increase. This result emphasizes the difference between natural exposure and a single experimental allergen challenge that was found to induce a greater increase in AHR. Particularly striking was a failure to detect a significant difference in AMP-induced AHR between salmeterol-treated and placebo-treated patients when they were challenged with this agent during the height of the pollen season. Since the AMP indirect challenge reflects bronchoconstriction caused by mast cell mediators, long-term salmeterol did not attenuate the chronic effects of mediators during the season and therefore did not function as an anti-inflammatory agent. Finally, ENO levels were increased in both treatment arms during the height of the pollen season, but there was neither an augmentative nor inhibitory effect in the salmeterol group. Taken together, these data, accumulated after long-term administration of salmeterol in pollen-allergic asthmatic patients during a well-defined period of seasonal exposure to pollen, confirm the safety profile of LABAs with respect to possible inflammatory or increased AHR effects. At the same time, however, based on the AMP challenge and the ENO results, the data also indicate that long-term use of an LABA alone will not provide a clinically effective anti-inflammatory effect. As the authors stipulate, possible mitigating variables, such as the time interval between the last dose of medication and pulmonary measurements, β2-agonist polymorphisms, or the complementary effects of inhaled glucocorticosteroid, were not fully addressed and may warrant further investigation. Nevertheless, this study reinforces the postulate that clinical management paradigms should be based on evidence derived from trials that closely simulate the natural course of disease.