Vaccines are considered as one of the most significant achievements of modern medicine. The first vaccine that protected animals against cancer is a vaccine designed for Marek’s disease virus. The most frequently used vaccine is the live-attenuated CVI988/Rispens (CVI) strain, which efficiently protects chickens against MD and prevents tumorigenesis. Interestingly, CVI expresses at least two isoforms of meq, the major oncogene of MDV. Meq is a basic leucine zipper (b-ZIP) protein consistently expressed in all MDV tumor and latently infected cells. We demonstrated that the longer isoform of meq strongly enhanced virus-induced pathogenesis and tumorigenesis, indicating that other mutations in the CVI genome contribute to virus attenuation. On the contrary, the shorter isoform completely abrogated pathogenesis, demonstrating that changes in the meq gene can indeed play a key role in virus attenuation. Although vaccinated chickens are protected against developing MD symptoms, the development of vaccines has raised questions about the potential consequences of vaccine-driven evolution of viruses. MDV is continually evolving towards higher virulence despite generations of vaccination. Circulating field strains have acquired numerous genomic mutations in the last 60 years. However, the evolutionary adaptations responsible for the vaccine breaks remained elusive. Distinct mutations in the meq oncogene arose every time that new vaccines were introduced that ultimately provided an evolutionary advantage. We tested recombinant viruses harbouring meq isoforms from different field strains in vivo. Here, we demonstrate that a few distinct mutations in the virus-encoded oncogene meq are responsible for the increase in virulence and oncogenicity. The viruses expressing the lower virulent meq isoforms showed reduced pathogenicity while in contrast the higher virulent meq isoforms dramatically increased pathogenesis in unvaccinated hosts. Only viruses harbouring the highest virulent meq isoform were able to break the vaccine barrier and cause tumors in vaccinated hosts - likely by overcoming innate cellular responses. Concomitantly, the polymorphisms in meq enhanced virus shedding into the environment putting naïve animals at greater risk.