Recent developments have furthered our understanding of endocardi- tis associated with intravenous drug use. Pathogenic differences between right- and left-sided endocarditis have clinically significant implications. Vancomycin may be suboptimal treatment for endocarditis due to methicillin-sensitive Staphylococcus aureus. Except for advanced disease, infection with the human immunodeficiency virus does not alter the course of endocarditis in drug users with both infections. Patients with left-sided endocarditis caused by Pseudornonas aeruginosa frequently suffer major complications; valve replacement is often required, but the optimal timing of surgical intervention is still debated.