As a result of the ongoing opioid epidemic, physicians have encountered increasing rates of drug-use-related native tricuspid valve infective endocarditis (DU-TVIE), a complex multi-faceted disease that is best managed by interdisciplinary teams. Despite the large number of patients with DU-TVIE, there is little data to support the optimal treatment strategy with respect to medical and surgical therapy. The recent introduction of percutaneous mechanical aspiration of tricuspid valve vegetations has added another treatment modality that is also of uncertain benefit. Here we review the literature on the management of DU-TVIE and highlight the multi-step treatment approach developed by the multidisciplinary endocarditis team at the University of Kentucky.