This paper reviews the development of the combination of modified vaccinia Ankara (MVA) to deliver the tumor-associated antigen 5T4 as a novel immunotherapeutic vaccine. The oncofetal antigen 5T4 is highly expressed in 80% of breast, kidney, colorectal, prostate and ovarian carcinomas, making it an ideal antigen for vaccine therapy. To date, more than 3000 doses of MVA-5T4 have been administered to colorectal, renal and prostate cancer patients, with rare occurrences of grade 3 or 4 vaccination-related adverse events being observed. Studies have demonstrated that MVA-5T4 is safe and highly immunogenic, both as monotherapy and in combination with other standard of care therapies. Although an immune response has been observed, antitumor activity has been modest or absent in clinical trials. A Phase III trial resulted in the development of an immune response surrogate that is to be applied to all future MVA-5T4 clinical trials. With minimal side effects and the ability to produce a strong immunogenic response, MVA-5T4 is a viable addition to the cancer therapy arsenal.