The importance of prevention in combatting the opioid crisis is clear identifying and implementing effective strategies to prevent the onset of opioid misuse and use disorder and reducing the need to treat disorders yields positive individual, societal, and financial benefits. In 2020, 9.5 million people aged 12 or older misused opioids in the past year (NSDUH, 2021), suggesting that there are millions of people whose trajectories could have been changed, had they been exposed to an effective prevention strategy. Currently funded HEAL studies are testing whether existing programs shown to prevent or treat non-opioid substance use disorders might generalize to opioids. However, there remain many gaps in knowledge about how to deploy prevention services. Often effective strategies are not adopted, implemented, or scaled-up, limiting their reach and impact. There is a critical need for research to develop innovative strategies to implement and sustain prevention services that are affordable, practical, sustainable, and designed in partnership with end-users. To address these gaps, we propose an RFA with multiple receipt dates calling for investigator-initiated research that will address priorities in the implementation and sustainability of prevention services, and the creation of a prevention infrastructure.