Soweto, South Africa’s largest urban township area, demonstrates both the successes of targeted research and service, and the multiple effects of constraints applied by a decade of governmental AIDS denial. Home to over 3 million residents, Soweto is characterized not only by antenatal HIV prevalence rates of 30%, but also by high rates of HIV testing and disclosure. Stigma and discrimination abound, despite 4 in 10 adults in Soweto ever having been tested for HIV, and almost 90% having disclosed their status, multivariate analysis demonstrates that gender, level of education, number of children, socioeconomic status, gender, and age significantly influence HIV stigma. The Soweto prevention of mother-to-child transmission (PMTCT) program is successful in identifying HIV⁺ women:  most pregnant women (98%) access voluntary counseling and testing (VCT), and 95% of HIV-infected women access PMTCT interventions, although initiating ongoing ART for eligible pregnant women is more difficult to achieve. Transmission rates were <5% in 2008, attributed to the addition of zidovudine (AZT) to single-dose nevirapine (NVP), and replacement feeding. The CHER study, conducted in Soweto and Cape Town, demonstrated that early access to ART in infants reduced mortality by 75%. Soweto has contributed to biomedical HIV prevention studies in both men and women, and demonstrated that access to circumcision in HIV prevention trials is feasible. Underserviced areas for treatment and prevention include adolescents, men-who-have-sex-with-men, and older women. Recent data show that 20.6% of men in a survey in Soweto were HIV infected. Risk factors for acquisition included younger age, alcohol use, and identifying as gay. Qualitative and quantitative data collected from in-school and out-of-school youth demonstrate that adolescent risky sexual behaviors are influenced by the media, lack of communication between children and their parents, substance abuse, transactional sex, and peer pressure. In a recent adolescent survey, most reside in female-headed households, more than half (55.5%) are sexually active. The mother of >1 in 10 adolescents has died, while the father of almost one-third have died. The burden of HIV has affected all facets of life in Soweto, and multi-component strategies that address both prevention and treatment will need to be implemented to address the epidemic in a systematic fashion.