Abstract Most persistent viral infections can be controlled, but not cured, by current therapies. Abrogated antiviral immunity and stable latently infected cells represent major barriers to cure. This necessitates life-long suppressive antiviral therapy. Achieving a cure for HIV, hepatitis B virus, Epstein Barr-virus, and others, requires novel approaches to facilitate the clearance of infected cells from the host. One such approach is to target host cell death pathways, rather than the virus itself. Here, we summarize recent findings from studies that have utilized therapeutics to manipulate host cell death pathways as a means to treat and cure persistent viral infections.