The United States is facing an opioid epidemic that is virulent in its lethality and includes morbidity and mortality related to prescription opioids. Overuse of another class of drugs— benzodiazepines—has received less media attention, but also poses the threat of tolerance, dependence, and death, especially in combination with opioids or alcohol. These negative outcomes are not distributed evenly over the population but are especially prevalent in vulnerable populations. One such vulnerable population comprises individuals with serious mental illness. Professionals who serve this population are challenged by an often-fragmented health care system to collaborate with patients and other professionals to reduce risks and improve outcomes. This article examines strategies for addressing risks associated with the use of benzodiazepines and opioids in this population within the context of an integrated interprofessional team. Recommendations include (a) building consensus on the team, (b) providing education for all stakeholders, and (c) enhancing care coordination and patient access to effective treatments.