Despite significant advances in antimicrobial therapy and an enhanced ability to diagnose and treat complications, infective endocarditis is still associated with substantial morbidity and mortality today, and its incidence has not decreased over the past decades. This apparent paradox may be explained by a progressive change in risk factors, leading to an evolution in its epidemiological and clinical features. In fact, new risk factors for endocarditis have emerged, such as intravenous drug abuse, diffusion of heart surgery procedures and prosthetic valve implantation, atherosclerotic valve disease in elderly patients, and nosocomial disease. Recently identified microorganisms (including Bartonella spp., Abiotrophia defectiva, and the HACEK group of bacteria [including Haemophilus spp., Actinobacillus spp., Cardiobacterium hominis, Eikenella corrodens and Kingella kingae]) are sometimes the cause of culture-negative endocarditis, and emerging resistant bacteria (such as methicillin- or vancomycin-resistant Staphylococci and vancomycin-resistant Enterococci) are becoming a new challenge for conventional antibiotic therapy. New therapeutic approaches need to be developed for the treatment of infective endocarditis caused by drug-resistant Gram-positive cocci, and some antimicrobial compounds recently introduced in clinical practice (such as streptogramins and oxazolidinones) may be an effective alternative, but further clinical studies are needed in order to confirm their effectiveness and safety. This review should help redefine the best therapeutic and preventive strategies against infective endocarditis.