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Viral pathogens play a prominent role in human health owing to their ability to rapidly evolve creative new ways to exploit their hosts. As elegant and deceptive as many viral adaptations are, humans and their ancestors have repeatedly answered their call with equally impressive adaptations. Here we argue that the coevolutionary arms race between humans and their viral pathogens is one of the most important forces in human molecular evolution, past and present. With a focus on HIV-1 and other RNA viruses, we highlight recent developments in our understanding of the human innate and adaptive immune systems and how the selective pressures exerted by viruses have shaped the human genome. We also discuss how the antiviral function of cellular machinery like RNAi and APOBEC3G blur the lines between innate and adaptive immunity. The remarkable power of natural selection is revealed in each host-pathogen arms race examined.