Cardiovascular disease accounts for a third of all deaths in the United States and is increasing throughout the developing world. Atherosclerosis has even been identified in ancient mummies, leading some to claim that heart disease is a “serial killer that has been stalking mankind for thousands of years”. Here, I reevaluate the relevance and significance of standard risk factors by considering the impacts of pathogens and immune function on atherosclerosis, highlighting findings from a longitudinal study among Tsimane Amerindians.