During the past year, a number of reports have described HIV-1 superinfection in human subjects, defined as the reinfection of an individual with a second heterologous strain of HIV-1. These reports have challenged the assumption that HIV-1-specific immune responses generated during primary infection are protective against subsequent infection and have raised concern, not only with respect to HIV-1-positive individuals engaging in unsafe sex but also from the standpoint of developing effective vaccines. Herein we review the published reports of HIV-1 superinfection and highlight studies providing additional insight into the potential for HIV-1 superinfections to affect the global epidemic.