More than half a million Americans became newly infected with human immunodeficiency virus (HIV) in the first decade of the new millennium. The domestic epidemic has had the heaviest impact on men who have sex with men and persons from racial and ethnic minority populations, particularly black persons. For example, black men who have sex with men represent <1% of the US population but 25% of new HIV infections, according to Centers for Disease Control and Prevention estimates published in 2008. Although black and Hispanic women constitute 24% of all US women, they accounted for 82% of HIV infections among women in 2005, according to data from 33 states with confidential name-based reporting. There is a nearly 23-fold higher rate of AIDS diagnoses among black women (45.5 diagnoses per 100,000 women) and a nearly 6-fold higher rate among Hispanic women (11.2 diagnoses per 100,000 women), compared with the rate among white women (2.0 diagnoses per 100,000 women). Investigators from the HIV Prevention Trials Network, a National Institutes of Health-sponsored collaborative clinical trials group, have crafted a domestic research agenda with community input. Two new domestic studies are in progress (2009), and a community-based clinical trial feasibility effort is in development (2010 start date). These studies focus on outreach, testing, and treatment of infected persons as a backbone for prevention of HIV infection. Reaching persons not receiving health messages and services with novel approaches to both prevention and treatment is an essential priority for control of HIV infection in the United States; our research is designed to guide the best approaches and assess the impact of bridging treatment and prevention.