Clinical decision support systems are intended to improve safety by providing clinicians with information about potential harms—principally harmful drug interactions and allergies—at the point of care. Analyzing more than 150,000 drug allergy warnings in the inpatient and outpatient settings within a single health care system, this study examined how often the warnings were overridden and the appropriateness of prescribers' reasons for doing so. Clinicians overrode 81% of warnings in hospitalized patients and 77% of alerts in outpatients. More than 96% of the overrides were judged appropriate by independent clinical reviewers. These proportions are similar to prior studies. A common appropriate reason for overriding was that the patient had actually tolerated the drug in question, leading the authors to call for improving the accuracy of allergy documentation in electronic medical records. A few classes of drugs accounted for a large proportion of overridden alerts, suggesting that enhancing the accuracy of allergy warnings for these drugs could significantly reduce the overall burden of alerts. Given that alert fatigue is an increasingly recognized patient safety hazard, creating tailored alerts could help clinical decision support systems achieve their potential to improve safety.