 This essay provides an overview of the current and emerging contexts of xylosines, a consistent part of the unregulated drug supply in recent months. It discusses major domains of harm, clinical and harm reduction strategies, public health and policy context, and epidemiology. The authors recommend interdisciplinary participation, investment in community-based harm reduction strategies, and improved drug supply surveillance to address the harms of xylosine. This article was authored by Claire M. Zagorski, Rebecca A. Hosey, Christopher Moroff, and others.