In the century and a quarter since William Osler delivered his famed Gulstonian lectures on endocarditis, continual advancements have been made in understanding and treating this disease. Here we have reviewed some key aspects of current knowledge in the areas of population epidemiology, host factors, microorganisms, and diagnosis. The advent of the ICE investigation provides the opportunity to further expand our understanding of IE by developing a very large, global database of IE patients whose clinical, echocardiographic, and microbiologic findings have been characterized with standard methodology. Further, ICE may serve as a rich source of material for investigators seeking to perform specific studies. Finally, the ICE infrastructure creates the opportunity for performing randomized trials to test therapeutic strategies. Although many obstacles remain to be overcome, ICE has created the opportunity for a quantum leap in our knowledge of IE over the next 25 years.