Substance use remains a leading cause of preventable death globally. A model of intervention known as screening, brief intervention, and referral to treatment (SBIRT) was developed decades ago to facilitate time- and resource-sensitive interventions in acute care and outpatient settings. SBIRT, which includes a psychosocial intervention incorporating the principles of motivational interviewing, has been shown to be effective in reducing alcohol consumption and consequences in unhealthy drinkers both in primary care and emergency department settings. Subsequently, SBIRT for unhealthy alcohol use has been endorsed by governmental agencies and professional societies in multiple countries. Although most trials support the efficacy of SBIRT for unhealthy alcohol use (McQueen et al. in Cochrane Database Syst Rev 8, 2011; Kaner et al. in Cochrane Database Syst Rev 2, 2007; O’Donnell et al. in Alcohol Alcohol 49(1):66–78, 2014), results are heterogenous; negative studies exist. A newer approach to screening and intervention for substance use can incorporate initiation of medication management at the index visit, for individuals willing to do so, and for providers and healthcare systems that are appropriately trained and resourced. Our group has conducted two successful trials of an approach we call screening, treatment initiation, and referral (STIR). In one trial, initiation of nicotine pharmacotherapy coupled with screening and brief counseling in adult smokers resulted in sustained biochemically confirmed abstinence. In a second trial, initiation of buprenorphine for opioid dependent individuals resulted in greater engagement in treatment at 30 days and greater self-reported abstinence. STIR may offer a new, clinically effective approach to the treatment of substance use in clinical care settings.