We shall focus on infective endocarditis due to Enterococcus spp and Staphylococcus aureus, both able to develop resistance to antibiotics with different mechanisms. Vancomycin-resistant strains produce some of the most challenging nososocomial infections. Enterococci develop resistance practically to all classes of antibiotics. Vancomycin-resistant strains, in the '90s, passed from 2% to more than 25%. Five types of vancomycin-resistance were reported (from van A to van E), linked to the presence of certain classes of genes regulating the production of abnormal precursors of peptidoglycan which inhibit the action of vancomycin. Staphylococcus aureus is a fearful organism whose infections can reach a mortality rate of 80%. In 1943, as soon as penicillin G was introduced into therapy, Staphylococcus strains producers of beta-lactamase were identified. After beta-lactamase-resistant penicillins were introduced into therapy, methicillin-resistant Staphylococcus strains appeared in the '60s. In 1996 the first strain of methicillin-resistant and vancomycin-resistant Staphylococcus aureus was isolated. In 2001, in Japan, the first case of infective endocarditis due to Staphylococcus aureus resistant to methicillin and non-responsive to vancomycin was described. The resistance is connected to an increased synthesis of the cell wall, which thickens reducing the activity of vancomycin.