Natural killer cells are a crucial component of the innate immune response to certain tumours and to various viruses, fungi, parasites and bacteria. HIV has infected more than 60 million people worldwide and has led to more than 23 million deaths. At present, there are ∼40 million people who are living with HIV infection, and there were 5 million new infections in 2004. As part of the innate immune system, natural killer cells might have an important role in host defence against HIV infection, as well as in the control of HIV replication in vivo. In this regard, it is important to understand how natural killer cells and HIV interact. This Review focuses on the role of natural killer cells in controlling HIV infection and on the impact of HIV and HIV-viraemia-induced immune activation on natural-killer-cell function.