The rapid emergence of novel psychoactive substances within the past decade has raised new concerns about the harms associated with unregulated drug use. Synthetic analogues-chemically related to established psychoactive substances like cannabis sativa and catha edulis-in particular have proliferated rapidly, allowing little opportunity for scientific research or the establishment of informal guidelines for safe use among consumers. To explore how synthetic substance use relates to other forms of use, this paper presents an analysis of polysubstance use among a sample of 676 people who use illicit substances in the United States. Participants were sampled from three greater metropolitan areas (Houston/Galveston, Texas; New York City; and New Orleans, Louisiana). Study researchers used cluster-type analyses to develop dendrogram visualizations of the interrelationships between substance types. Results suggest a considerable variation in substance and polysubstance use patterns across states in the U.S. Polysubstance use clustered around well-observed combinations like MDMA/cannabis and cocaine/heroin. Synthetic cannabinoids and cathinones showed no strong clustering with other substances. High rates of binge drinking among users of other substances further support the importance of interventions sensitive to the clinical challenges of polysubstance use.