The ability of members of the APOBEC3 (A3) family of proteins to confer intrinsic immunity to retroviral infection was recognized in several studies. More specifically, A3 proteins are cytidine deaminases (CDAs) that cause hypermutations of nascent retroviral genomes by deamination of cytidine residues. Although A3 proteins can restrict the replication of HIV, this inhibition is overcome by the viral infectivity factor (Vif). Inhibitory effects of APOBEC proteins are not limited to HIV but extend to other viruses and endogenous mobile genetic elements that share a reverse transcription process analogous to that of exogenous retroviruses. In sharp contrast, another conundrum of A3 proteins is that they inhibit viral replication even in the absence of CDA activity and recent advances have defined the inhibition of reverse transcriptase (RT) catalyzed DNA elongation reactions by A3 proteins. Together, these proteins provide strong and immediate intracellular immunity against incoming pathogens and restrict the movement of mobile genetic elements protecting the genome.