The extreme spike in overdose deaths and substance-exposed pregnancies that communities across the United States have suffered in recent decades, combined with worsening maternal morbidity and mortality outcomes and a global pandemic, have created a perfect storm for women of reproductive age who experience problematic substance use, behavioral health concerns, poverty and trauma. Health care and safety net service providers who treat and support this population are at the center of this storm and are in need of large scale, system-level solutions to successfully care for their patients and clients in the context of an ever-changing and increasingly complex service environment. This workshop will explore promising system change strategies to improve perinatal health, safety and recovery outcomes for the mom-baby dyad and mitigate the harmful impact of substances, particularly opioids. We will also discuss lessons learned that can be applied in any setting to create a more responsive and empathic approach to care for families at the crossroads of multiple systems.