Although infective endocarditis (IE) is not the most frequent infection seen in intravenous (IV) drug abusers (IVDAs), health care providers should always regard it as a possible diagnosis in this population. Many researchers have tried to elucidate the clinical, epidemiologic, immunologic and pathogenetic aspects of this entity. Right-sided endocarditis accounts for almost 10% of all IE episodes and has been most commonly interrelated with IV use of illicit substances. On the other hand, recent reports have proposed that left-sided valve participation is seen more often now than in the past. While, our progress in medicine, new diagnostic criteria and especially modern imaging techniques have broadened our ability to recognize IE, there are still some gray areas regarding right-sided IE. Our aim is to comprehensively review the clinical features and complications and also the possible pathogenetic and immunologic mechanisms implicated in IE patients who are injecting illicit substances.