The origin and rise of social inequalities that are a feature of the post-Neolithic society play a major role in the pattern of disease in prehistoric and contemporary populations. We use the concept of epidemiological transition to understand changing ecological relationships between humans, pathogens and other disease insults. With the Paleolithic period as a baseline, we begin with ecological and social relationships that minimized the impact of infectious disease. Paleolithic populations would have retained many of the pathogens that they shared with their primate ancestors and would have been exposed to zoonoses that they picked up as they adapted to a foraging existence. The sparse mobile populations would have precluded the existence of endemic infectious disease. About 10,000 years ago, the shift to an agricultural subsistence economy created the first epidemiological transition, marked by the emergence of infections, a pattern that has continued to the present. Beginning about a century ago, some populations have undergone a second epidemiological transition in which public health measures, improved nutrition and medicine resulted in declines in infectious disease and a rise in non-infectious, chronic and degenerative diseases. Human populations are entering the third epidemiological transition in which there is a reemergence of infectious diseases previously thought to be under control, and the emergence of novel diseases. Many of the emerging and reemerging pathogens are antibiotic resistant and some are multi-antibiotic resistant. Inequality continues to widen within and between societies, accelerating the spread of emerging and reemerging diseases.