The Eight Americas Study divides the U.S. population into eight distinct groups with different epidemiologic patterns and mortality experience. The Eight Americas are Asians (America 1), below-median-income whites living in the Northland (America 2), middle America (America 3), poor whites living in Appalachia and the Mississippi Valley (America 4), Native Americans living on reservations in the West (America 5), black middle-America (America 6), poor blacks living in the rural South (America 7), and blacks living in high-risk urban environments (America 8). Life expectancy for males in America 8 is 21 years lower than life expectancy for females in America 1. For males, the gap between America 1 and America 8, 16.1 years, is as large as the gap between Iceland with the highest male life expectancy in the world and Bangladesh. Even in Americas 5, 6, 7, and 8, U.S. child mortality is in the middle of the range defined by the Organization of Economic Cooperation and Development (OECD) countries. For young and middle-aged males and females, however, mortality experience in the disadvantaged Americas is up to two times worse than the worst OECD country. The enormous excess of young and middle-aged mortality is largely due to chronic disease death. Based on the World Health Organization Comparative Risk Assessment project, we expect the major risks in the United States to be tobacco, alcohol, obesity, blood pressure, and cholesterol. Risk factor analysis using Behavioral Risk Factor Surveillance System data for the Eight Americas suggests that the pattern for tobacco, alcohol, and obesity is distinct for each America. Currently available data in the public domain do not provide an adequate basis to assess levels of blood pressure and cholesterol in the Eight Americas. To tackle disparities in the United States, public health will need to increase its focus on chronic diseases in young and middle-aged Americans. In particular, if blood pressure and cholesterol are confirmed as major contributors to current mortality patterns, innovative strategies such as the Polypill and unique individual and population approaches need to be explored.