Bacterial endocarditis is difficult to cure because of poor penetration of antibiotics into infected vegetations, altered metabolic state of bacteria within the lesion, and absence of adequate host-defense cellular response, that could cooperate with antibiotic action. Two main aspects are discussed for their effect on human therapy: (1) the kinetics of antibiotic diffusion into vegetations, with a special reference to the data obtained with autoradiography, and (2) the specificity of some pharmacodynamic aspects of antibiotics in endocarditis, including the clinical consequences of these two parameters on antibiotic dosing regimens and length of therapy.