Viruses that persist in infected hosts must evolve successful strategies to avoid recognition by the immune system. The primary player in antiviral immune surveillance is the CD8⁺cytotoxic T lymphocyte (CTL), and the battle drawn between the CTLs and viruses is the focus of this review. In this struggle, viruses can follow multiple distinct pathways. For example, DNA viruses often adopt the strategy of encoding proteins that interfere with the immune response along routes of antigen presentation. Such interference prevents the viral peptide from binding to the major histocompatibility complex (MHC) class I glycoprotein; therefore, no virus–MHC complex forms for recognition by antiviral CTLs. RNA viruses, having fewer genes, generate swarms of quasispecies that can contain mutated viral proteins. When such mutants occur in viral peptides presented to the MHC protein or the residue recognized by the CTL receptor, CTL recognition and activation fail. If, instead, the mutation occurs in the viral peptide flanking sequence, the infected cell may not process the viral peptide from the cytosol to the endoplasmic reticulum. Viruses can also directly or indirectly attack dendritic cells and CD4⁺or CD8⁺T lymphocytes, other routes that interfere with immune functions. Dendritic cells are the primary professional antigen-presenting cells and are critical for the activation of CTL responses. CD4⁺T lymphocytes provide help for long-term CD8⁺CTL activity and are necessary for its maintenance. Consequently, interference with either dendritic or CD4⁺cell types constitutes yet another way that viruses can disable the immune response and persistently infect their host.