Recent research has implicated inflammatory processes in the pathophysiology of a wide range of chronic degenerative diseases, even though inflammation has long been recognized as a critical line of defense against infectious disease. But current scientific understandings of the links between chronic low-grade inflammation and diseases of aging are based primarily on research in high income nations with low levels of infectious disease, and high levels of overweight/obesity. From a comparative and historical point of view, this epidemiological situation is relatively unique, and may not capture the full range of ecological variation necessary to understand the processes that shape the development of inflammatory phenotypes. The human immune system is characterized by substantial developmental plasticity, and a comparative, developmental, ecological framework is needed to undertand the complex associations among early environments, the regulation of inflammation, and disease. This presentation discusses results from recent studies in the Philippines and lowland Ecuador that reveal low levels of chronic inflammation despite higher burdens of infectious disease, and point toward nutritional and microbial exposures in infancy as important determinants of inflammation in adulthood. By shaping the regulation of inflammation, early environments moderate responses to inflammatory stimuli later in life, with implications for the association between inflammation and chronic diseases. A comparative human biology approach suggests that chronic inflammation may be a “disease of affluence”, and it points toward promising directions for future research on inflammation and the prevention and treatment of chronic disease.