Therapeutic vaccines for chronic infections and cancer are needed. Challenges faced by therapeutic vaccines differ from those of preventative vaccines. Whereas the latter target a naive immune system, the former have to readjust an antigen-experienced immune system that is subverted due to sustained exposure to antigen. E1-deleted adenoviral vectors have succeeded preclinically as preventative vaccines and are now in clinical trials. Their potential as therapeutic vaccines for diseases caused by chronic virus infections or virus-associated malignancies remains to be explored in more depth and may require modifications to circumvent negative immunoregulatory pathways that develop following chronic infections or during tumour progression.