The efficacy of screening and brief intervention (SBI) for drug use in primary care patients is largely unknown. Because of this lack of evidence, US professional organizations do not recommend it. Yet, a strong theoretical case can be made for drug SBI. Drug use is common and associated with numerous health consequences, patients usually do not seek help for drug abuse and dependence, and SBI has proven efficacy for unhealthy alcohol use. On the other hand, the diversity of drugs of abuse and the high prevalence of abuse and dependence among those who use them raise concerns that drug SBI may have limited or no efficacy. Federal efforts to disseminate SBI for drug use are underway, and reimbursement codes to compensate clinicians for these activities have been developed. However, the discrepancies between science and policy developments underscore the need for evidence-based research regarding the efficacy of SBI for drug use. This article discusses the rationale for drug SBI and existing research on its potential to improve drug-use outcomes and makes the argument that randomized controlled trials to determine its efficacy are urgently needed to bridge the gap between research, policy, and clinical practice.