This dissertation is a study of the social, scientific, political and rhetorical origins of extensively drug-resistant tuberculosis (XDR-TB) and the ability of a technical medical term, in concert with local clinical and government responses, to influence global biomedical action. XDR-TB, a form of tuberculosis that is resistant to most anti-tuberculosis drugs, was first creatively named and defined in 2005 in the context of a global laboratory survey documenting increasing tuberculosis drug resistance patterns around the world. In 2006, XDR-TB attracted international attention after a deadly cluster of drug-resistant tuberculosis was discovered in the rural South African town of Tugela Ferry, KwaZulu-Natal. International media and global health workers, responding to this news, defined XDR-TB as a critical threat to global health emanating from Southern Africa. As this dissertation shows, the association of XDR-TB with South Africa shaped the global response to XDR-TB, tying it closely to HIV/AIDS and linking it to the well-known history of South African AIDS denialism and public health inaction. The careful scrutiny given to South African XDR-TB by global public health experts profoundly impacted South African government responses to XDR-TB at the national, provincial, and regional levels. This detailed, multifaceted case study of global health knowledge in-the-making is based on nearly two years of fieldwork in South African clinical and community settings and interviews with international and South African tuberculosis researchers, policy makers, clinicians, administrators and patients. Widely circulated representations of XDR-TB are juxtaposed with the personal experience of South African nurses and local government administrators to make the case that responsibility for and control of successful global health interventions is more broadly distributed than common conceptions of global health research imply. In addition, this research uses published documents, unpublished policy literature, and promotional materials to trace how medical, public, and political understandings of XDR-TB in South Africa changed over time and across geographical space. This research changes our understanding of the politics and practices of health interventions in Africa by linking together activities ranging from the crafting of scientific publication, to global policy decision making, local public resource allocation and in-home nursing care.