As the third decade since AIDS was first recognized comes to an end, extraordinary advances have occurred in the understanding, treatment, and prevention of HIV infection and AIDS. As a result of these successes, it is now time to focus on future challenges. Paramount among these is reaching the goal of truly controlling and ultimately ending the HIV and AIDS pandemic. To that end, AIDS researchers and public health personnel worldwide are aggressively pursuing 3 key areas of scientific research. Given the availability of highly effective therapeutic regimens for HIV infection, the first challenge is efficiently identifying a maximum number of HIV-infected persons through voluntary HIV testing and initiating antiretroviral therapy (ART). Second, scientists are trying to develop a cure for HIV infection, which would alleviate the need for lifelong ART. Finally, preventing new cases of HIV infection, which currently number approximately 2.6 million per year globally, is critical to any attempt to end this pandemic. This article addresses each of these challenges and provides directions for the future.