Traditional ethics provide insight, but often fall short of guiding the complex biomedical ethical concerns of research conducted in developing countries. The need to create research within a framework that is appropriate to the social, medical, and political context of developing countries is examined through the current AIDS pandemic in sub-Saharan Africa. A specific case study focuses on this issue. Over 70 percent of the 40 million people with HIV/AIDS live in sub-Saharan Africa. With at least one in five African adults infected with the disease, sub-Saharan Africa is now acknowledged as the epicenter of HIV/AIDS. The scale and scope of the disease in the environment of a developing economy presents unique issues that challenge the role and practices of traditional ethics in healthcare research programs. Medical research within developing countries, particularly for HIV/AIDS, requires a distinctive approach. For these populations, investigators must incorporate new thinking into traditional biomedical research ethics which will address the role of innovation; access to treatment; the impact of fear, stigma, and denial; concerns around autonomy for vulnerable populations; capacity building; and sustainable care to communities. Since May 1999, Secure the Future, a philanthropic program that focuses on care and support for women and children infected and affected by HIV/AIDS, has attempted to fulfill these ethical concepts in its processes. The program is a public and private sector partnership between governments, communities, practitioners, academia, and Bristol-Myers Squibb Company to respond to AIDS in five countries in sub-Saharan African countries: Botswana, Lesotho, Namibia, South Africa, and Swaziland. To ensure symmetry between ethical principles and local context, collaborative projects undergo a comprehensive review process. This includes review and approval by a national secretariat to ensure projects support objectives of national policies and local communities; approval by an ethics committee comprised of participating institutions; blinded peer review; and an examination by an external advisory board comprised of local and international medical experts, persons living with AIDS (PLWA), religious communities, governments, and nongovernmental organizations (NGOs). An independent monitor also oversees the approved programs. Cost-effective and practical interventions against HIV/AIDS must encompass ethical approaches appropriate to the contexts of the respective developing countries. Lessons learned to date are to focus on innovation; establish unassailable ethical standards that are sensitive to local contexts; ensure transparent communications among partners and the broader community; and build sustainable capacity.