This article describes U.S. income inequality and 100-year national and 30-year regional trends in age- and cause-specific mortality. There is little congruence between national trends in income inequality and age- or cause-specific mortality except perhaps for suicide and homicide. The variable trends in some causes of mortality may be associated regionally with income inequality. However, between 1978 and 2000 those regions experiencing the largest increases in income inequality had the largest declines in mortality (r= 0.81, p < 0.001). Understanding the social determinants of population health requires appreciating how broad indicators of social and economic conditions are related, at different times and places, to the levels and social distribution of major risk factors for particular health outcomes.