Since its creation, U.S. Immigration and Customs Enforcement’s (ICE’s) Homeland Security Investigations (HSI) has had a longstanding commitment to safeguard public safety and protect people from transnational criminal organizations that threaten communities across the United States and beyond. Nowhere is this more relevant—or being more urgently pursued—than in HSI’s sustained and recently enhanced efforts to combat the opioid crisis that is gripping the United States. While the root causes of the current crisis are complex, the solution HSI has developed and implemented to help stem the tide of opioids coming into communities is relatively simple and straightforward—leverage the unique authorities and broad resources of HSI to disrupt, dismantle, and defeat the transnational criminal organizations and distribution networks responsible for the current crisis by identifying and targeting upper echelon traffickers, seizing their assets, and holding them accountable for the destruction they are responsible for. To accomplish this, HSI is determined to target these individuals and organizations wherever they are located, including within the deep recesses of cyberspace. As a result, those who traffic opioids, particularly within the dark web, are a top priority of HSI. Dangerous and often fatal substances such as fentanyl, carfentanil, and other synthetic opioids, as well as heroin and illicitly obtained prescription opioids, are increasingly being distributed online via the dark web, requiring new and innovative strategies by HSI and its law enforcement partners. These newly formed strategies have been developed, implemented, and continuously refined to maximize the probability of success and have resulted in significant accomplishments, though the challenge remains substantial.