Antiretroviral (ARV) drugs have become the cornerstone of care and treatment for AIDS in North America, Brazil, and Europe. Twenty years into the epidemic, and more than 10 years after the introduction of ARV's, effective global treatment of AIDS, particularly in sub-Saharan Africa where the epidemic is most concentrated, is an extraordinary challenge. Guidelines and experience in anti-microbial prophylaxis, prescription and monitoring of ARV's in resource-rich countries should inform the efforts to scale-up AIDS care and treatment in Africa. Here, we review the considerable experience of ARV treatment acquired largely in the Americas and Europe, and the fledgling clinical trials and observational studies in Africa. Implementation of safe, effective, and equitable access to ARV's in Africa should be cognizant of the guidelines for ARV treatment in the Northern countries. Careful observation and operational research to accrue more African data, and evaluate regional and local solutions to this daunting challenge, will identify new approaches to scaling-up of ARV treatment.