The incidence of injection drug use-associated infective endocarditis has been increasing rapidly over the last decade. Patients with drug use-associated infective endocarditis present an increasingly common clinical challenge with poor long-term outcomes and high reinfection and readmission rates. Their care raises issues unique to this population, including antibiotic selection and administration, indications for and ethical issues surrounding surgical intervention, and importantly management of the underlying substance use disorder to minimize the risk of reinfection. Successful treatment of these patients requires a broad understanding of these concerns. A multidisciplinary, collaborative approach providing a holistic approach to treating both the acute infection along with effectively addressing substance use disorder is needed to improve short-term and longer-term outcomes.