The goals of management of COPD include reducing exposure to risk factors; improving lung function, exercise tolerance, and quality of life; and decreasing exacerbations and mortality. Pharmacologic treatments, such as inhaled β2-agonists, anticholinergics, and inhaled corticosteroids, are widely used to help achieve these goals. In addition to efficacy, medication safety is an important consideration in selecting COPD treatments. Clinical trials conducted in support of the regulatory review and approval process establish the general efficacy and tolerability of pharmacologic treatments for COPD, and these data are reflected in product labeling. Following approval, further research continues to provide more data with longer follow-up and in broader settings than feasible in clinical trials. These data add to our knowledge of the efficacy of medications. Understanding medication safety requires assessment of the quality and appropriateness of study design, as well as knowledge of study findings, and is of paramount importance in making sound clinical judgments in the treatment of patients with COPD. In recent years, a wealth of data on COPD medications has been published from different sources, including randomized clinical trials, meta-analyses, systematic reviews, and observational studies. This review discusses important considerations in interpreting data from different types of studies, summarizes the tolerability profile of COPD medications established in preapproval studies, and discusses new findings from more recent postapproval data.