Despite improvements in medical and surgical therapy, prosthetic valve endocarditis is still associated with a severe prognosis, and remains a diagnostic and therapeutic challenge. Diagnosis of prosthetic valve endocarditis is more difficult than that of the native valve endocarditis and the application of Duke criteria is less useful in this setting. Therapeutic strategies are not guided by evidence-based recommendations and are mainly based on a careful prognostic evaluation, which allows the identification of high-risk subgroups. Continuous effort have to be made to detect early this severe complication of valve replacement and to prevent it using systematic prophylaxis.