Vaccinia virus (VV), the virus smallpox vaccine, replicates in the cytoplasm of infected cells. The intracellular movement of this large virus would be inefficient without specific transport mechanisms; therefore, VV uses microtubules for movement during both entry and egress. In addition, the dissemination of virus from infected cells to adjacent cells is promoted by the polymerization of actin beneath cell surface virions to drive virus particles away from the cell. Last, the roles of different VV particles in virus movement within and between hosts are discussed.