As humans move from the natural environment in which we evolved into modern urban settings, there are striking increases in chronic inflammatory and psychiatric disorders. To understand and eventually take control of this phenomenon we have to understand how humans, and in particular our immune systems, evolved in partnership with microorganisms in the environment and in our own bodies. Humans are holobionts, composed of human cells containing the human genome passed on via the germline, but also a much larger number of microbial cells acquired from mother, family members, and the environment. This microbiota provides signals involved in the development of essentially all organ systems, including the brain, and provides data and signals that regulate metabolism and the immune system. The immune system evolved to perform the dual functions of managing this microbiota, while simultaneously protecting us from pathogens. By considering the evolution of the immune system and the ways in which lifestyle changes have altered our exposures to, and colonisation by microorganisms, we can identify the crucial factors leading to the modern urban pattern of disease.