Phylogenetic analyses indicate that HIV-1 arose from a zoonotic infection from chimpanzees. Moreover, HIV-1 has been transmitted to humans on at least three separate occasions, and each of those zoonotic events has given rise to an independent group of HIV-1 sequences referred to as HIV-1 M (main), O (outlier), and N (non-M, non-O). Remarkably, the frequency of these viruses in the current human population is vastly different, with around 30 million people living with HIV-1 M group infection and about 10,000 with O group infection. Only a handful of N group infections have ever been described. Thus, O and N group viruses are not pandemic, and in the absence of HIV-1 M group infections, HIV/AIDS would be a rare tropical disease. It is obviously of great importance to understand the differences between the viruses that underlie their different frequencies. What are the features of pandemic HIV-1 that make it so much more successful? Now, Sauter and colleagues show that, although pandemic HIV-1 M group has successfully adapted its Vpu protein to antagonize the human antiviral restriction factor tetherin, the O group viruses have not. Could the ability to escape tetherin explain the different frequencies of pandemic and nonpandemic HIV-1 strains?