Immunization against smallpox was always considered successful if a skin lesion formed at the site of vaccination. As researchers are looking to use vaccinia virus, the virus in the smallpox vaccine, in other therapeutics and preventative vaccines, it is important to characterize more extensively the mechanisms by which the immune system controls vaccinia virus and thereby protects against smallpox. Researchers have now determined that immune cells known as CD4+ T cells have an important role in controlling skin lesion size at sites of revaccination.