Inflammation of the inner layer of the heart, especially the valvular endothelium, chordae tendinae and mural endocardium was first recognized almost 350 years ago. Over the years it has had many names, but is now generally designated infective endocarditis (IE) and has an associated infectious agent. A sterile vegetative process can also affect the valves and is usually referred to as Libman-Sacks endocarditis. The developments of medical science that allowed for our understanding of this entity included refinement of the autopsy, medical microscopy, microbiology, and in recent years, molecular studies. Some observations were misleading but clarification particularly followed the reports of Morgagni, Osler and Libman. As understanding of the pathobiology of infective endocarditis grew so did the effectiveness of therapy. This paper provides a detailed history of the development of the concept of Infective endocarditis citing many key morphological observations and concludes with brief comments about current concepts of pathogenesis as well as a few remarks about therapy.