Our laboratory is focused on uncovering and understanding the mechanisms of immunosuppression that potentiate dysfunctional immunity during persistent virus infections. We then implement this information to develop therapies that restore immune function to purge these infections. Many of the same pathways that suppress antiviral immunity during persistent infections are also being identified as playing a key role in inhibiting the immune response from eliminating many cancers. By comparing the mechanisms that suppress the immune response in multiple chronic disease states, we propose that the most fundamental mechanisms can be identified. In addition to immunosuppression, persistent virus infections are associated with chronic inflammation that is increasingly being recognized to further exacerbate immune exhaustion and promote disease progression. Although these two seemingly opposing programs of inflammation and immunosuppression co-exist and each associated with worsened disease during persistent virus infections and cancer, their relationship is unclear. Thus, by understanding the underlying mechanisms of immunosuppression and their relationship to chronic inflammation, it will then be possible to devise therapeutic approaches to harness the immune response to fight multiple chronic diseases.