Shigella flexneri are invasive Gram negative bacteria that cause bacillary dysentery in humans. It is a significant pathogen due to the high morbidity among children in developing countries coupled with multi-drug resistance and a lack of vaccine. Shigella are acquired via the faecal-oral route and invade the host colonic epithelium via microfold cells. After inducing pyroptosis of the resident macrophages in the follicle associated epithelium, the bacteria are released into the basolateral compartment, and invade enterocytes. Post invasion, Shigella escapes from the endosome to initiate replication and cell to cell spread within the epithelium. Concurrently the NF-κB pathway is activated through Nod1. NF-κB is a key regulator in favouring a pro-survival response early in the infection that allows the bacteria time to replicate and disseminate into the neighbouring cells. This is later skewed towards a pro-death pathway, resulting in further inflammatory responses that eventually eliminate the bacteria. In this study, we probed components of the apoptotic and necrotic pathways with specific inhibitors in an attempt to identify components crucial for Shigella induced cell death in epithelial cells. HeLa cells were infected with Shigella bacteria at a multiplicity of infection (m.o.i.) of 1000, and cell death was measured four hours later by assaying LDH (lactate dehydrogenase) release. Inhibition of caspases (with Z-VAD-fmk) and components of the necroptotic pathway (with necrostatin-1, necrostatin-7) resulted in a small, albeit significant reduction in cell death. Inhibition of Drp1 with mdivi-1 and by siRNA silencing reduced cell death significantly. Drp1 is a mitochondrial GTPase, important for regulating mitochondrial division. Mitochondrial division represents an important checkpoint in the execution of apoptotic and necrotic cell death. Mitochondrial fragmentation in HeLa cells was observed during Shigella infection, and treatment of the infected cells with mdivi-1 restored the mitochondrial network. In this study, we have identified Drp1 and mitochondria, as key and novel components in Shigella induced epithelial cell death.