Complex relationships between human and animal species have resulted in human–animal interfaces that have promoted cross-species transmission, emergence and eventual evolution of a plethora of human pathogens. Remarkably, most of the characteristics of these interfaces have been established long before the end of our species pre-historical development, to be relentlessly shaped throughout the history of our own and animal species. More recently, changes affecting the modern human population worldwide and their dramatic impact on the global environment have taken domestication, agriculture, urbanization, industrialization, and colonization to unprecedented levels. This has created new global multi-faceted human–animal interfaces, associated with major epidemiological transitions, accompanied by an unexpected rise of emerging and re-emerging infectious diseases in humans, that all have their origin in animal reservoirs. Until the beginning of the last century, infectious diseases were the major cause of mortality of humans. Around 1900 infectious diseases caused about fifty percent of human deaths in the western world. In the following decades, this percentage decreased to less than a few percent. This was largely due to the implementation of public health measures such as sewage installment and development of clean drinking water systems, but also to development of vaccines and antimicrobials. Major successes in this regard were the eradication of smallpox and rinderpest through well-orchestrated vaccination campaigns in humans and cattle, respectively. Such successes prompted policymakers and scientists to predict that infectious diseases of humankind and of their domestic animals would eventually be brought under control in the industrialized world. Paradoxically the following decades confronted the world with an ever-increasing number of emerging or re-emerging infectious diseases, some causing true human or animal pandemics. Pathogens spilling over from wildlife reservoirs, either directly or via intermediate hosts, were at the basis of most of these disease outbreaks. Striking examples in humans were the emergence of AIDS from chimpanzees, avian flu from migratory birds, and SARS, MERS, and Ebola from bat reservoirs. A complex mix of predisposing factors in our globalizing world, linked to major changes in our societal environment and global ecology, collectively created opportunities for viruses and other pathogens to infect and adapt to new animal and/or human hosts. This paved the way for the unprecedented spread of infections in humans and animals with dramatic consequences for public and animal health, animal welfare, food supply, economies, and biodiversity. It is important to realize that due to the complex and largely interactive nature of the predisposing factors, it is virtually impossible to predict what the next pathogen threat will be, from where it will come and when it will strike. However better understanding of the underlying processes may eventually lead to predictions that would improve our preparedness for outbreaks in humans and animals. Importantly, the increased emergence of viral infections is largely paralleled by medical, veterinary, technological, and scientific progress, continuously spurred by our never-ending combat against pathogens. Investment in better understanding the human–animal interfaces will therefore offer a future head start in the never-ending battle against infectious diseases of humans.