The magnificence and diversity of African wildlife have fascinated humankind since centuries and nourished the concept of exoticism within in human history since colonial times. The concept of wildlife-livestock interface in Africa is well known since then the nineteenth century when pathogens, such as rinderpest or African animal trypanosomiasis were circulating between both compartments and challenging the development of early livestock development. Since then, Africa has been the origin of many infectious pathogens circulating at the interface with wildlife such as Foot and Mouth Disease, African Swine Fever, Ebola, or HIV, that continue to challenge livestock and human health within its boundaries and also across the planet. During the last decades, drivers of global transformation such as climate change, population growth, and human development are having a tremendous impact on Africa's natural ecosystems and exponentially increasing opportunities of pathogen spillover between wildlife, livestock, and human populations with unprecedented impacts of each one of those compartments. At the same time, Africa is also confronted with the challenge to manage its wildlife resources sustainably through new forms of exploitation (tourism, commercial bushmeat trade, game ranching, game farming) that generate much-needed sources of income and protein and facilitate new pathways of interaction at the interface and new challenges for disease control and monitoring. This chapter reviews the changes that are transforming Africa's interface, the conjunction of drivers that generate new interactions between wildlife, domestic animals, and humans, and the problems and consequences and challenges to mitigate and monitor old and new risks of disease transmission.