Chronic obstructive pulmonary disease (COPD), which affects > 210 million individuals worldwide, places primary care practitioners at the forefront of diagnosing and managing COPD, and preventing adverse drug reactions (ADRs) associated with COPD medications. Therefore, it is essential that practitioners understand the safety profiles of these medications. They should also be aware of the host factors and any preexisting comorbidities in their patients that may impact the safety and efficacy of the prescribed therapy. Drug safety information obtained from randomized controlled trials, observational studies, and meta-analyses should be analyzed to assess the risk-benefit to a patient, since the majority of ADRs associated with COPD medications are predictable, and are avoidable with judicious use of these drugs. This article discusses the different medications available for COPD management and the factors affecting their safety based on current evidence.