North America is facing an opioid epidemic and growing illicit drug supply, contributing to growing numbers of injection drug use-related infective endocarditis (IDU-IE). Patients with IDU-IE have high early and late mortality. Patients with IDU-IE more commonly present with right-side IE compared with those with non-IDU IE, and a majority are a result of Streptococcus aureus. Although most patients can be successfully managed with intravenous antibiotic treatment, surgery is often required in part owing to high relapse rates, potential treatment biases, and more aggressive pathophysiology in some. Multidisciplinary management as endocarditis teams, including not only cardiologists and cardiac surgeons, but also infectious disease specialists, drug addiction experts, social workers, neurologists, and neurosurgeons, is essential to best manage substance use disorder and facilitate safe discharge to home and society. Structural and population-level interventions, such as harm-reduction programs, are necessary to reduce IDU-IE relapse rates in the community and other IDU-related health concerns, such as overdoses. In this review, we describe the pathophysiologic, clinical, surgical, social, and ethical characteristics of IDU-IE and their management. We present the most recent clinical guidelines for this condition and discuss existing gaps in knowledge to guide future research, practice changes, and policy interventions.