Restriction factors are natural cellular proteins that defend individual cells from viral infection. These factors include the APOBEC3 family of DNA cytidine deaminases, which restrict the infectivity of HIV-1 by hypermutating viral cDNA and inhibiting reverse transcription and integration. HIV-1 thwarts this restriction activity through its accessory protein virion infectivity factor (Vif), which uses multiple mechanisms to prevent APOBEC3 proteins such as APOBEC3G and APOBEC3F from entering viral particles. Here, we review the basic biology of the interactions between human APOBEC3 proteins and HIV-1 Vif. We also summarise, for the first time, current clinical data on the in vivo effects of APOBEC3 proteins, and survey strategies and progress towards developing therapeutics aimed at the APOBEC3–Vif axis.