Concerns about the safety of long-acting β2-agonist (LABA) therapy, has led to the appearance of multiple publications and recommendations. This review critically examines the available clinical evidence and safety requirements for LABA use. On the basis of nearly 20 systematic reviews and databases, the authors conclude that LABA monotherapy significantly increases the risk of asthma-related adverse effects. We also conclude that the use of LABAs concomitantly with inhaled corticosteroids (ICS) significantly reduces asthma hospitalisations and is not associated with life-threatening events and asthma-related deaths, especially when concurrent use of LABAs and ICS can be reasonably assured (use of a single inhaler device). An appropriate clinical study would require an extremely large sample, making it impractical. Finally, some of the new US Food and Drug Administration (FDA) recommendations have caused confusion and do not appear to be fully evidence based. Although limited by low statistical power, the evidence supports the use of LABAs plus ICS in a single inhaler device (to increase adherence and reduce the potential use of LABA monotherapy) for all patients (not only children) with moderate to severe asthma.