To defend against external pathogens, metazoan organisms have evolved numerous defenses that generally fall within the innate and adaptive immune responses. Considerable effort continues to focus on developing a vaccine to manipulate the adaptive immune system to protect against or control HIV-1. However, recent advances in our understanding of the innate immune system have revealed that cells have a potent intrinsic antiretroviral defense in the form of APOBEC3G, which is a member of a larger family of cytidine deaminases that are active against HIV-1 and other retroviruses. Insights into how the action of A3G is circumvented by HIV-1 through the action of its Vif protein, and the surprising mechanisms by which A3G is regulated within the cell, offer exciting new opportunities for developing novel anti-HIV-1 therapies that exploit this intrinsic antiretroviral system.