It is extremely important for biodiversity conservation that protected areas are resilient to a range of potential future perturbations. One of the least studied influences on protected area resilience is that of disease. We argue that wildlife disease (1) is a social-ecological problem that must be approached from an interdisciplinary perspective; (2) has the potential to lead to changes in the identity of protected areas, possibly transforming them; and (3) interacts with conservation both directly (via impacts on wild animals, livestock, and people) and indirectly (via the public, conservation management, and veterinary responses). We use southern African protected areas as a case study to test a framework for exploring the connections between conservation, endemic disease, and social- ecological resilience. We first define a set of criteria for the social-ecological identity of protected areas. We then use these criteria to explore the potential impacts of selected diseases (foot-and-mouth disease, anthrax, malaria, rabies, rift valley fever, trypanosomiasis, and canine distemper) on protected area resilience. Although endemic diseases may have a number of direct impacts on both wild animals and domestic animals and people, the indirect pathways by which diseases influence social-ecological resilience also emerge as potentially important. The majority of endemic pathogens found in protected areas do not kill large numbers of wild animals or infect many people, and may even play valuable ecological roles; but occasional disease outbreaks and mortalities can have a large impact on public perceptions and disease management, potentially making protected areas unviable in one or more of their stated aims. Neighboring landowners also have a significant impact on park management decisions. The indirect effects triggered by disease in the human social and economic components of protected areas and surrounding landscapes may ultimately have a greater influence on protected area resilience than the direct ecological perturbations caused by disease.