In most countries, tuberculosis caused by Mycobacterium bovis is mainly a disease of domestic cattle and can be controlled successfully by means of a test-and-slaughter program. Once the infection spills over into a wild animal species with maintenance host potential, conventional measures are no longer sufficient to provide effective control. In South Africa, African buffaloes (Syncerus caffer) represent the most important maintenance host for M. bovis. Apart from transmitting the disease to predators and scavengers that feed on them, buffalo also serve as a source of infection to other wildlife species through environmental contamination. In several countries, it was shown that an infected wildlife reservoir that interacts with livestock causes frequent herd breakdowns and substantial economic losses to the agricultural sector. The outbreak of tuberculosis in free-ranging wildlife populations thus poses a huge challenge on long-term management and control strategies to prevent spillover into other wildlife, especially endangered, wildlife species and domestic livestock.