Regulated cell death is a powerful anti-viral mechanism capable of aborting the virus replicative cycle and alerting neighbouring cells to the threat of infection. The biological importance of regulated cell death is illustrated by the rich repertoire of host signalling cascades causing cell death and by the multiple strategies exhibited by viruses to block death signal transduction and preserve cell viability. Vaccinia virus (VACV), a poxvirus and the vaccine used to eradicate smallpox, encodes multiple proteins that interfere with apoptotic, necroptotic and pyroptotic signalling. Here the current knowledge on cell death pathways and how VACV proteins interact with them is reviewed. Studying the mechanisms evolved by VACV to counteract host programmed cell death has implications for its successful use as a vector for vaccination and as an oncolytic agent against cancer.