Clinical decision support systems are widely utilized to improve patient safety by alerting providers to potential medication errors and other safety concerns. However, these alerts are frequently overridden by clinicians and contribute to alert fatigue. Researchers sought to assess the impact of a transition from a legacy electronic health record system to a commercial system on provider reactions to drug–drug interaction alerts in the ambulatory setting. There was a sixfold increase in the burden of interruptive alerts with adoption of the commercial system, and clinician acceptance for the most severe interaction alerts decreased from 100% to 8.4%. The authors suggest that the timing of alerts in the workflow process, user-interface design factors, and the inability to distinguish between more and less severe drug interactions all contributed to the decline in provider acceptance after adoption of the new system. A previous WebM&M commentary discussed a case in which a patient experienced an adverse drug event after a clinician overrode a prescribing alert.