Infective endocarditis remains a serious and potentially fatal disease. Even with appropriate therapy, mortality rates remain at about 10% to 20%. Common errors in treatment include starting antibiotics before obtaining at least three blood cultures, failing to use bactericidal drugs, stopping therapy too early, and delaying heart surgery when it is indicated. The epidemiology of endocarditis will continue to evolve, and we will see more cases that are hospital acquired, more cases associated with the presence of cardiac support devices, and cases associated with line-related bacteremia. Therefore, organisms associated with endocarditis will also likely evolve. We will see more cases due to multiresistant organisms (eg, vancomycin-resistant enterococci, glycopeptide-resistant staphylococci, and multidrug-resistant gram-negative rods) as well as yeast and fungi.