The impact of clinical decision support systems on improving medication safety has been limited by a lack of standardized and tailored alerts to warn prescribing clinicians about dangerous drug–drug interactions. Progress in this area has stalled owing to disagreement between clinicians and system designers along with concerns about liability if warnings are deployed incorrectly. This study reports on the development of a consensus list of 15 high-severity, clinically significant drug–drug interactions, arrived at through an expert panel approach that included input from pharmacists, physicians, electronic medical record (EMR) developers, and developers of online clinical knowledge bases. The authors recommend that alerts to prevent these interactions should be implemented in all EMRs.