Current models of infectious disease in the Pleistocene tell us little about the pathogens that would have infected Neanderthals (Homo neanderthalensis). High quality Altai Neanderthal and Denisovan genomes are revealing which regions of archaic hominin DNA have persisted in the modern human genome. A number of these regions are associated with response to infection and immunity , with a suggestion that derived Neanderthal alleles found in modern Europeans and East Asians may be associated with autoimmunity. Independent sources of DNA-based evidence allow a re-evaluation of the nature and timing of the first epidemio-logic transition. e paradigm of the first epidemiologic transmission, the hypothesis that epidemic disease did not occur until the transition to agriculture, with larger, denser and more sedentary populations, has been essentially unchallenged since the 1970s. Our views of the infectious disease environment of the Pleistocene period are heavily influenced by skeletal data and studies of contemporary hunter-gatherers. New genetic data – encompassing both hosts and pathogens – has the power to transform our view of the infectious disease landscape experienced by Neanderthals in Europe, and the AMH with whom they came into contact. e Pleistocene hominin environment cannot be thought of as free from infectious disease. It seems likely that the first epidemiologic transition, envisaged as part of the package of the Holocene farming lifestyle, may be fundamentally different in pace or scope than has previously been suggested. is paper demonstrates how high quality genomic data sets can be used to address questions arising from the ecological context that shaped the co-evolutionary relationship we share with infectious diseases. We analyse the evidence for infectious disease in Neanderthals, beginning with that of infection-related skeletal pathologies in the archaeological record, and then consider the role of infection in hominin evolution. We have synthesised current models on the chronology of emergence of notable European disease packages and analyse what implications this evidence has for the classical model of the first epidemiologic transition. Using emerging data from Neanderthal palaeogenomics and combining this with fossil and archaeological information we reexamine the impact of infectious diseases on human populations from an evolutionary context. We argue that the first epidemiologic transition in Eurasia was not as tightly tied to the onset of the Holocene as has previously been assumed. ere is clear evidence to suggest that this transition began before the appearance of agriculture and occurred over a timescale of tens of thousands of years. We suggest that the epidemiological transition was not, as has been thought since the 1970s, a phenomenon of the human shi to sedentary agriculture during the Holocene but a much older and more complex process that involved at least two species of humans. e origin of resistance to infectious disease has a much deeper timeframe and is highlighted by the ingression of Neanderthal DNA into modern human lineages. e transfer of pathogens between human species may also have played a role in the extinction of the Neanderthals. Our analysis of the genomes of archaic hominins provides evidence of pathogens acting as a population-level selection pressure, causing changes in genomes that were passed on to descendants and preserved in the genomes of modern Eurasians. e analysis of ancient genomes demonstrates that human behavioural patterns (in this case a shi to agricultural subsistence) should not be used as an ecological proxy to explain shiing trends in the co-evolutionary relationship between pathogens and human populations. is work is available on BioRxiv: http://dx.