Infective endocarditis of the right-side heart valves occurs commonly in injection drug users. Although a variety of hypotheses have been put forward to explain this clinical observation, no single hypothesis is adequate. In this article, basic scientific, clinical, and microbiological data on this topic are presented. It is apparent that no clear unifying mechanism emerges to explain the well-documented clinical predilection for the infection of the right-side heart valves in this population. Further investigation of this topic utilizing large international clinical registries may help to clarify matters further.