Vaccinia virus is the most extensively studied member of the poxvirus family due to its role as a vaccine in the eradication of smallpox. Over the past thirty years, interest has turned to the potential of Vaccinia as an oncolytic virus; it has inherent preference to replicate in cancer cells, it infects both primary and metastatic tumours and also induces anti-tumour immunity. However, trials to date have been disappointing when Vaccinia is delivered as a monotherapy, and focus has moved to combining it with other treatments to optimise its oncolytic effect. The Way lab has developed a pro-apoptotic strain of Vaccinia (ΔΔVF) that lacks two anti-apoptotic viral proteins, Vaccinia growth factor (VGF) and F1. In addition, through a whole genome siRNA screen, a group of genes have been identified that, when inhibited in the host cell, further increase ΔΔVF induced cell death. I have shown that ΔΔVF induces more cell death than Western Reserve (WR), the strain from which it originates, in HeLa cells and a panel of human and murine ovarian cancer cells. In addition, I have demonstrated that when TBK1 (a hit from the screen) is inhibited, there is a dramatic increase in ΔΔVF induced cell death. While exploring the mechanism behind this finding, I have discovered that Vaccinia infection induces early, transient autophagy. This autophagy is dependent on the presence and activity of TBK1 and is lost when TBK1 is inhibited. From these findings, I propose a model whereby the loss of early autophagy, an antiviral response, promotes apoptotic cell death in response to infection. When this is coupled with ΔΔVF infection, a pro-apoptotic virus, the resulting apoptotic cell death is particularly striking.