In December 2005, the UNAIDS and WHO reported that the global epidemic known as acquired immunodeficiency syndrome (AIDS) has claimed the lives of more than 25 million adults and children over the past 26 years. These figures included an estimated 3.1 million AIDS-related deaths in 2005. Despite enormous efforts to control the spread of human immunodeficiency virus (HIV) new infection rates are on the rise. An estimated 40.3 million people are now living with HIV, including 4.9 million new infections this past year. Nearly half of new HIV infections are in young people between the ages of 15 and 24. While drug therapies have helped sustain the lives of infected individuals in wealthy regions, they are relatively unavailable to the poorest global regions. This includes sub-Saharan Africa which has approximately 25.8 million infected individuals, more than triple the number of infections of any other region in the world. It is widely believed that the greatest hope for controlling this devastating pandemic is a vaccine. In this review, we will discuss the current state of DNA-based vaccines and how they compare to other vaccination methods currently under investigation. We will also discuss innovative ideas for enhancing DNA vaccine efficacy and the progress being made toward developing an effective vaccine.