HIV-1 genetic variability within individuals and populations plays a central role in the HIV pandemic. Multiple zoonotic transmissions of SIV to humans have resulted in distinct HIV lineages in humans which have further diversified within the population over time. High rates of mutation and recombination during HIV reverse transcription create a genetic diversity in the host which is subject to selection pressures by the immune response and antiretroviral treatment. The global distribution of HIV genetic variants and the impact of HIV diversity on pathogenesis, transmission and clinical management are reviewed. Finally, the key role of escape mutations in the immune response to HIV is discussed as well as the major challenge which HIV-1 diversity poses to HIV vaccine development.