The first step in the diagnosis of infective endocarditis is a high level of clinical suspicion. Only rarely are all the classic signs of infective endocarditis, namely fever, a new cardiac murmur, splenomegaly, anemia and embolic phenomena, found. Every organ system can be involved by embolic or immunologic complications. We have to look specially for manifestations in skin and mucosa, CNS, kidney, locomotor system and lungs. The clinical spectrum has changed over the last decades. More elderly patients, patients with prosthetic heart valves and i.v. drug users are affected. The traditional classification into acute and subacute infective endocarditis has been replaced by a classification based on the microbiological etiology or on the involved valve (native, prosthetic, left- or right sided). In particular, the clinical presentation of right-sided infective endocarditis differs from the left-sided one. A diagnosis of infective endocarditis has to be considered in every patient with unexplained fever or a multisystem disease. A definite diagnosis of infective endocarditis rests on a multidisciplinary approach that involves the clinician and the echocardiography and microbiology laboratories.