The ongoing COVID-19 crisis has emphasized more than ever the relevance of wildlife as a potential source of pathogens for other species, including humans, and the potential importance that interactions with wildlife can have on global health. Nevertheless, in the veterinary world, the concept of wildlife as a potential reservoir and source of pathogens detrimental to livestock production and health has been known for centuries. Well-known examples of livestock diseases in which the interface with wildlife plays, or has played, an important role include rinderpest, avian influenza, foot and mouth disease (FMD), and African swine fever (ASF). Rinderpest, caused by a morbillivirus of the family Paramyxoviridae, is one of only two diseases that have been globally eradicated (the other being smallpox in humans), after having caused major disease outbreaks in domestic and wild artiodactyl species for centuries. After a globally coordinated eradication campaign, the World Organisation for Animal Health (OIE) and the Food and Agriculture Organization (FAO) of the United Nations announced in 2011 that rinderpest virus had been eliminated from livestock, thus declaring global freedom from this disease (Hamilton et al., 2017). Circulation of rinderpest virus in endemic regions in wild susceptible species was an important consideration in the eradication campaign, and lack of recognition of wildlife reservoirs was one of the factors to which failure of initial campaigns in the 1960s and 70s was attributed (Morens et al., 2011). Other diseases, such as ASF and FMD, are still endemic and expanding across different regions of the world. FMD is estimated to be endemic in 77% of the global livestock population, in Africa, Asia, and some parts of South America (OIE, 2021a) and ASF is becoming endemic in Africa, Europe, Asia, and some parts of Oceania (OIE, 2021b). Efforts to control or eradicate these diseases are challenging, particularly in those areas where wild reservoir hosts contribute to their maintenance and spread. African swine fever virus (ASFV) has been known for more than a century to be maintained in the soft tick-warthog sylvatic cycle in natural savannah environments in East and Southern Africa. Occasional interactions between ASFV-infected ticks and domestic pigs have facilitated the dissemination of several ASFV genotypes into the domestic pig value-chain in Africa and subsequently into other parts of the world (Dixon et al., 2020). During the currently ongoing pandemic of ASF, the wild boar population in Europe has played a central role in the propagation of the virus into new areas. While most ASF spread appears to occur within domestic pig populations due to anthropogenic factors, incursions of ASFV into low biosecurity domestic pig farming systems from wild boar are also important (Brookes et al., 2021). Likewise, transboundary spread of FMD in susceptible domestic livestock such as cattle and pigs is commonly mediated by anthropogenic factors, such as movement of infected livestock, or the feeding of infected products to susceptible species (Di Nardo et al., 2011). However, in East and Southern Africa, the African buffalo interface plays an important role in maintaining FMD virus (FMDV) strains and disseminating them to adjacent susceptible livestock populations (Jori and Etter, 2016). These examples provide only a snapshot illustration of the potential role of wildlife on livestock disease and demonstrate the importance of the wildlife–livestock interface. At a planetary scale, several factors act as major drivers of increased wildlife–livestock interactions at these interfaces (Magouras et al., 2020). Critical drivers include the need to feed an ever-increasing world human population, which has altered the way in which livestock are farmed, the way in which we interact with the ecosystem, and climate change. These drivers not only increase the intensity and frequency of interactions between wildlife and potential spillover populations (e.g., humans and domesticated animals such as livestock) but also facilitate new transmission pathways for potential emerging pathogens. Some of the impacts of these interactions have been well-described in the literature, particularly those affecting livestock production and health. However, these interactions can also have very significant and devastating effects on wildlife populations and the environment. Importantly, circulation of undetected pathogens in the domestic and wild animal compartments also provides opportunity for the development of potentially dangerous emerging infectious diseases. In this review, we provide an overview of the drivers of wildlife–livestock interactions and their potential impacts on terrestrial livestock production. We define wildlife as any domesticated or non-domesticated species that is free-ranging and does not depend on mankind for food or reproduction. In addition, we present and discuss the major tools and methods to reduce wildlife–livestock contact and to mitigate its health implications, including biosecurity measures and the approaches and potential solutions for improved cohabitation between livestock and wildlife to encourage biodiversity and reduce negative impacts such as disease spillover.