Despite severe punishments and high rates of inequitable incarceration, unprecedented numbers of opioid-related deaths persist in the United States. The US has implemented few policies that align needs of communities, needs of individuals with opioid use disorder (OUD), and clinical evidence. Evidence-based harm reduction practices hold promise to help advance domestic approaches to thinking of OUD treatment as a human right, but successful implementation of harm reduction interventions relies heavily on care continuity and can still be thwarted by a so-called “War on Drugs.” This theme issue follows our August 2020 issue, Opioids and Public Health, and specifically considers harm as a concept in need of careful, case-specific attention and reduction as an intervention or set of interventions that are part of a safety net to curb opioid-related morbidity and mortality.