Disease management along the boundaries of wildlife reserves is a growing conservation problem worldwide, as infected wildlife can migrate outside protected areas and pose a threat to livestock and human health. The bison Bison bison population in Yellowstone National Park has long been infected with Brucella abortus, the bacterium causing bovine brucellosis. Concern over migratory bison transmitting B. abortus to cattle herds on lands adjacent to Yellowstone has led to proposals for bison vaccination. Model simulations suggest that vaccination is unlikely to eradicate B. abortus from Yellowstone bison but could be an effective tool for reducing the level of infection and eliminating unpopular management practices such as lethal culling. The culling of Yellowstone bison to reduce the risk of brucellosis transmission to cattle is negatively affecting long-term bison conservation because of difficulties in diagnosing actively infected animals. Age-specific serology and B. abortus culture assays from slaughtered bison were used to develop a diagnostic tool to estimate whether particular animals are infective. Findings suggest that active B. abortus infection is age-dependent, which allows true infection probabilities to be estimated based on age and quantitative diagnostic tests. Active brucellosis infection was associated with below-average nutritional condition, with the intensity of B. abortus infection being influenced by seasonal reductions in dietary protein and energy. The reproductive strategy of Yellowstone bison is linked with the seasonal availability of food, which increases bison fitness but may have consequences for B. abortus infection. Seasonal food restriction may also influence the ability of vaccinated bison to recall protective immune responses when later exposed to B. abortus. The rate of fat metabolism was an important factor influencing cell-mediated responses. Thus, individual variation and the seasonal availability of food may reduce vaccine efficacy when vaccination is applied at the population level. Consequently, effective management practices will require a diverse range of integrated methods, which include maintaining separation of livestock and wildlife, managing habitat to reduce brucellosis transmission, and reducing disease prevalence in wildlife. The long-term success of these management practices will depend on sound science and support of the stakeholders involved.