The use of potent antiretroviral drugs has led to successful treatment of HIV infection in most high-income countries. However, therapy remains largely unaffordable to the resource-limited world, particularly to countries in sub-Saharan Africa. The disparity and subsequent disease burden are devastating to the poorly resourced countries, hence creating a greater demand for international collaboration. This review outlines key examples of emerging HIV pharmacotherapy issues, challenges, and priorities within resource-limited settings in order to lay groundwork for potential enchancement of international research collaboration efforts. The prevalence and distribution patterns of HIV infection and sociocultural factors found in sub-Saharan African settings are discussed. Challenges include drug financing, drug distribution infrastructure, and government commitment to responding to the HIV pandemic. Priorities include prevention of HIV transmission, management of pediatric patients, availability of affordable medicines, and addressing concerns over the quality of medicines. The potential for the effective international collaboration is enhanced when expertise and resources from the developed world are combined with an understanding of the unique priorities of resource-limited settings.