Bovine tuberculosis (BTB) is an exotic disease invading the buffalo population (Syncerus caffer) of the Kruger National Park (KNP), South Africa. We used a sex and age-structured epidemiological model to assess the effectiveness of a vaccination program and define important research directions. The model allows for dispersal between a focal herd and background population and was parameterized with a combination of published data and analyses of over 130 radio-collared buffalo in the central region of the KNP. Radio-tracking data indicated that all sex and age categories move between mixed herds, and males over 8 years old had higher mortality and dispersal rates than any other sex or age category. In part due to the high dispersal rates of buffalo, sensitivity analyses indicate that disease prevalence in the background population accounts for the most variability in the BTB prevalence and quasi-eradication within the focal herd. Vaccination rate and the transmission coefficient were the second and third most important parameters of the sensitivity analyses. Further analyses of the model without dispersal suggest that the amount of vaccination necessary for quasi-eradication (i.e. prevalence < 5%) depends upon the duration that a vaccine grants protection. Vaccination programs are more efficient (i.e. fewer wasted doses) when they focus on younger individuals. However, even with a lifelong vaccine and a closed population, the model suggests that >70% of the calf population would have to be vaccinated every year to reduce the prevalence to less than 1%. If the half-life of the vaccine is less than 5 years, even vaccinating every calf for 50 years may not eradicate BTB. Thus, although vaccination provides a means of controlling BTB prevalence it should be combined with other control measures if eradication is the objective.