In addition to the conventional innate and acquired immune responses, complex organisms have evolved an array of dominant, constitutively expressed genes that suppress or prevent viral infections. Two major cellular defenses against infection by retroviruses are the Fv1 and TRIM5 class of inhibitors that target incoming retroviral capsids and the APOBEC3 class of cytidine deaminases that hypermutate and destabilize retroviral genomes. Additional, less well characterized activities also inhibit viral replication. Here, the present understanding of these 'intrinsic' immune mechanisms is reviewed and their role in protection from retroviral infection is discussed.