Intradermal injection of vaccinia virus in the ear pinnae of mice provides a model of dermal infection and vaccination. The key features of this model are the appearance of a lesion on the surface of the ear that can be measured as a clinical sign of disease and substantial growth of virus in the infected skin in the absence of systemic spread. In addition, infected ears can be easily removed to allow virological, histological, and cellular analyses. Finally, evaluation of the roles of virus (and presumably also host) genes in vaccinia virus pathogenesis in the intradermal model can yield different results than similar experiments using other routes and may reveal otherwise unknown functions.