Most cases of endocarditis are caused by nonenterococcal streptococci. Some of these organisms are classified as relatively resistant to penicillin on the basis of minimum inhibitory concentrations (MICs) greater than 0.1-0.2 microgram/mL. Almost all authorities recommend that endocarditis caused by relatively resistant streptococci be treated with high doses of penicillin combined with 2-6 weeks of an aminoglycoside rather than the potentially shorter, less toxic, and more flexible regimens used for exquisitely sensitive streptococci (MIC, less than 0.1-0.2 microgram of penicillin/mL). The data to support this recommendation are limited and inconclusive. We review the relevant clinical experience, experimental models, and theoretical considerations. Penicillin alone is probably adequate therapy for most cases of native valve endocarditis caused by relatively resistant streptococci; in certain patients, it may be the preferred treatment.