Oncolytic viruses (OV) are promising anti-cancer agents, capable of selectively replicating in tumour cells and killing them. Chemotherapy, on the other hand, remains the backbone of current cancer treatment, although it is limited by a narrow therapeutic index, significant toxicity, and frequent acquired resistance. There is an increasing body of evidence on a variety of chemotherapeutic agents that have been shown to be synergic with OV and result in increased response rates in preclinical studies. Several possible mechanisms have been proposed to mediate the enhanced anti-tumour activity of such combination treatment. Moreover, it has been shown how prodrug- activating enzymes armed oncolytic viruses promote synergy with prodrugs. In the present review we summarise the current knowledge concerning the benefits of the combination of OV and cytotoxic drug treatment and discuss the translational opportunities such therapeutic synergies have in the fight against cancer.