The field of oncolytic viral therapy has undergone a major shift in focus in the last few years. Less research has been directed at making incremental improvements in original vectors based mainly on strains of adenovirus and HSV; instead a variety of different viral strains have been suggested as potential backbones for future oncolytic viruses (including Newcastle disease virus, reovirus, vesicular stomatitis virus, polio virus, retrovirus, Sindbis virus, picornavirus, mumps and measles virus), with many of these progressing to clinical trials. Of these, vaccinia virus represents a particularly promising candidate. It possesses a variety of intrinsic molecular properties suitable for an oncolytic virus (such as rapid life cycle and lysis of infected cells, and an ability to infect various cell types), in addition to undergoing extensive study both in the laboratory and in the clinic. Although not a natural human pathogen, there are extensive data on the effects of vaccinia infection in humans. Preclinical models incorporating new oncolytic vaccinia strains, as well as data from the first clinical trials that have utilized the next-generation oncolytic vaccinia strains for the potential treatment of cancer have been described.