The interest in therapeutic cancer vaccines has caught enormous attention in recent years due to several breakthroughs in cancer research, among which the finding that successful checkpoint blockade treatments reinvigorate neo-antigen-specific T cells and that successful adoptive cell therapies are directed towards neo-antigens. Neo-antigens are cancer-specific antigens, which develop from somatic mutations in the cancer cell genome that can be highly immunogenic and are not subjected to central tolerance. As the majority of neo-antigens are unique to each patient's cancer, a vaccine technology that is flexible and potent is required to develop personalized neo-antigen vaccines. In vitro transcribed mRNA is such a technology platform and has been evaluated for delivery of neo-antigens to professional antigen-presenting cells both ex vivo and in vivo. In addition, strategies that support the activity of T cells in the tumor microenvironment have been developed. These represent a unique opportunity to ensure durable T cell activity upon vaccination. Here, we comprehensively review recent progress in mRNA-based neo-antigen vaccines, summarizing critical milestones that made it possible to bring the promise of therapeutic cancer vaccines within reach.