Induction of cell invasion is common to both poxviral infection and oncogenic progression. When compared to cancer however, regulation of invasiveness is poorly understood during poxvirus infection, despite its role in dissemination and spread of virus particles. Actin tail formation is an important step in the vaccinia virus lifecycle, facilitating release and superrepulsion of enveloped virions into neighbouring cells. Actin tail formation relies on the phosphorylation of viral proteins by Abl and Src kinases to recruit the Arp2/3 complex, initiating actin nucleation. This actin polymerisation machinery is also important for the formation of invadopodia – invasive cellular projections commonly seen in metastatic cancer cells. We have used a fluorescent gelatin degradation assay to examine the effects of vaccinia virus infection on cell invasion and invadopodia formation. The ability of different vaccinia virus strains to induce an invasive phenotype was compared to examine the role of actin-based motility. In addition, potential cellular regulators of invasion were targeted for siRNA knockdown to explore interactions between the host cell and viral proteins that lead to induction of invasion.