One potentially promising strategy to control chronic infections such as human immunodeficiency virus, hepatitis B virus, and hepatitis C virus is therapeutic vaccination, which aims to reduce persisting virus by stimulating a patient's own antiviral immune responses. However, this approach has fallen short of expectations, because antiviral T cells generated during chronic infections often become functionally exhausted and thus do not respond properly to therapeutic vaccination. Therefore, it is necessary to develop a therapeutic vaccine strategy to more effectively boost endogenous T‐cell responses to control persistent viral infections. Studies to elucidate the cause of impaired T‐cell function have pointed to sustained inhibitory receptor signaling through T‐cell expression of programmed death 1 (PD‐1). Recently, another inhibitory molecule, cytotoxic T lymphocyte antigen 4 (CTLA‐4), and also an immunosuppressive cytokine, interleukin 10 (IL‐10), have been reported to be potential factors of establishing immune suppression and viral persistence. Blocking these negative signaling pathways could restore the host immune system, enabling it to respond to further stimulation. Indeed, combining therapeutic vaccination along with the blockade of inhibitory signals could synergistically enhance functional CD8⁺ T‐cell responses and improve viral control in chronically infected mice, providing a promising strategy for the treatment of chronic viral infections. Furthermore, not only the ablation of negative signals but also the addition of stimulatory signals, such as interleukin 2 (IL‐2), might prove to be a potentially promising strategy to augment the efficacy of therapeutic vaccination against chronic viral infections.