Vaccinia virus (VACV) is the live vaccine that was used to eradicate smallpox, a feat achieved in 1977 and certified by the World Health Organization in 1980. Since 1980, research with VACV has continued in part because of the development of techniques to genetically manipulate VACV and create live VACV strains expressing foreign genes. These recombinant VACVs can be used as live vaccines against other infectious diseases and cancers, and as a powerful tool to study virus pathogenesis, immunology, cell biology, and virus-host interactions. This short article describes two examples of how enduring interest in VACV has revealed new features of VACV biology and the immune system.