Although many potential drug– drug interactions (DDIs) are clinically inconsequential, DDIassociated harm does occur. The magnitude of harm caused by DDIs is not precisely known, but research suggests that DDIs may be a significant public health issue. Americans are frequently exposed to clinically important DDIs despite advances in health information technology designed to warn clinicians about potentially harmful drug combinations. System design issues and problems with the DDI evidence base are partly responsible for exposure to these potential hazards. The nation’s health care system is undergoing a transformation to improve the quality, safety, and efficiency of care. Under the Health Information Technology for Economic and Clinical Health Act of 2009, implementation of electronic DDI and drug–allergy checking is one of the core “meaningful-use” objectives that providers must meet to qualify for financial incentives when they adopt certified electronic health record technology. With the meaningfuluse regulation and other initiatives promoting electronic prescribing (e-prescribing), there is an even greater need to improve the generation, evaluation, and integration of DDI evidence into clinical decisionsupport (CDS) systems to maximize the value of these technologies. Lisa E. Hines, Pharm.D., is Clinical Research Pharmacist, Center for Health Outcomes and PharmacoEconomic Research; John E. Murphy, Pharm.D., is Professor and Associate Dean, Department of Pharmacy Practice and Science; Amy J. Grizzle, Pharm.D., is Assistant Director, Center for Health Outcomes and PharmacoEconomic Research; and Daniel C. Malone, Ph.D., is Professor, Department of Pharmacy Practice and Science, College of Pharmacy, University of Arizona, Tucson. Address correspondence to Dr. Malone at the Department of Pharmacy Practice and Science, College of Pharmacy, University of Arizona, 1295 North Martin Avenue, P.O. Box 210202, Tucson, AZ 85721-0202 (malone@ pharmacy.arizona.edu). Funded by a grant (1R13HS018307-01) from the Agency for Healthcare Research and Quality (AHRQ), U.S. Department of Health and Human Services (HHS); the opinions expressed are those of the authors and do not reflect the official position of AHRQ or HHS. Additional support provided by Epocrates, First DataBank, Gold Standard, LexiComp, Micromedex, PharmaSURVEYOR, and Wolters Kluwer. The authors have declared no potential conflicts of interest.