Ebola virus and HIV present challenges for vaccine development because natural immunity to these viruses is difficult to find, and there are no immune correlates of protection in humans. Modern molecular genetic, virologic and immune analyses have been used to rationally identify promising approaches based on animal model and human clinical studies. Improved vaccine candidates have been defined for HIV, and a promising Ebola vaccine have conferred protection in non-human primates. Further evaluation in humans will allow an assessment of their potential efficacy and point the way to the development of more successful vaccines.