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Although the application of major biomedical advances has yielded spectacular results for individual health, there has been little improvement in the health of whole populations. There is a "back to the future" irony in the fact that at the inception of the 21st century, the eruption and spread of a multitude of "old" and "new" infectious diseases has become the most serious global threat to the health of humankind. At this historical juncture, the United States is the country with the most potential for favorably influencing global health and health care. Although there are historical, cultural, economic, and political factors that impede the United States from rising to this challenge, there is both a moral imperative and a rational long-term self-interest basis for the U.S. medical profession and government to exercise leadership in facing the health challenges of tragic and genocidal proportions that threaten everyone in an increasingly interdependent world.