Cancer immunotherapy recently has emerged as a revolutionary method in oncology. It takes the help of the body's immune system in fighting against tumor cells. Amongst the various approaches, DNA and mRNA vaccines are novel modalities with the potential to revolutionize cancer treatment. They represent one such approach that can result in potent immune responses against tumor-specific antigens. The few but serious translation bottlenecks at the clinical level have been related to stability, in vivo distribution, and efficient delivery systems for DNA and mRNA vaccines. It is against this salient background that this chapter takes readers through recent success stories of DNA and mRNA vaccines, right from the formulation of the vaccine to delivery mechanisms, stability, and bioavailability in cancer immunotherapy. The further challenges that are discussed in this chapter are those of effect in vivo distribution and how such challenges impact therapeutic efficacy. In addition, the new emerging technologies for in vivo distribution and opportunities for optimization of emerging vaccines to clinical use are approached, with the main focus placed on new delivery platforms. The aim of this chapter is to help understand the current landscape and future directions toward DNA and mRNA vaccines in designing more effective and personalized cancer therapies.