Screening, Brief Intervention, and Referral to Treatment (SBIRT) is a comprehensive and integrated approach to the delivery of early intervention and treatment services through universal screening for persons with substance use disorders and those at risk. This paper describes research on the components of SBIRT conducted during the past 25 years, including the development of screening tests, clinical trials of brief interventions and implementation research. Beginning in the 1980s, concerted efforts were made in the US and at the World Health Organization to provide an evidence base for alcohol screening and brief intervention in primary health care settings. With the development of reliable and accurate screening tests for alcohol, more than a hundred clinical trials were conducted to evaluate the efficacy and cost effectiveness of alcohol screening and brief intervention in primary care, emergency departments and trauma centers. With the accumulation of positive evidence, implementation research on alcohol SBI was begun in the 1990s, followed by trials of similar methods for other substances (e.g., illicit drugs, tobacco, prescription drugs) and by national demonstration programs in the US and other countries. The results of these efforts demonstrate the cumulative benefit of translational research on health care delivery systems and substance abuse policy. That SBIRT yields short-term improvements in individuals' health is irrefutable; long-term effects on population health have not yet been demonstrated, but simulation models suggest that the benefits could be substantial.