As the country struggles to address an epidemic of alcohol and drug overdose, a wide-ranging category of chemical substances known as synthetic drugs have provoked a new sense of public urgency over the past decade. Synthetic cannabinoids, a heterogeneous and evolving set of synthetic compounds that act on endogenous cannabinoid receptors, have become particularly popular among adolescents due to their relative ease of access and reputation as a “legal high.” The Baltimore City Health Department has worked to combat the recent surge in synthetic drug use through a major public awareness campaign, legislative reform, and retailer engagement and compliance initiative. In doing so, the city has built a coalition of clinicians, advocates, retailers, educators, legislators, and community members to fight synthetic cannabinoid use in Baltimore City. In this commentary piece, we offer strategies from our work and from that of our colleagues across the country for clinicians and communities fighting to stem the tide of recreational synthetic cannabinoid use.