Tuberculosis is a serious chronic disease of humans and animals caused by members of the Mycobacterium tuberculosis complex. While M. tuberculosis affects primarily humans, Mycobacterium bovis has a wide range of host species including wild and domestic animals and humans. This chapter investigates the role of different host species in the transmission of tuberculosis at various animal/human interfaces. While drivers and modes of zoonotic TB transmission are reviewed, a broad spectrum of complexities hampering the eradication of this disease are highlighted. The most important constraints, next to factors related to pathogen-host interactions such as HIV co-infection and multidrug resistance of MTBC strains, are socio-economic shortcomings in the control of bovine tuberculosis in the cattle population as well as traditional customs and habits related to the consumption of milk and other animal products.