There exists a paramount need for effective vaccines against cancer, TB, malaria, HIV, HCV, and other chronic infections. The hope for long-term control of these important diseases ultimately may depend upon development of potent T cell-based therapeutic vaccines. However, current, licensed vaccines or capable vaccine platforms have not made a substantial impact on treatment of these conditions, likely due in part to poor CD8 T cell immune induction. Thus, identification of novel adjuvants to be deployed to induce effective T responses is an important area of research in T cell based vaccines. While multiple adjuvants have been readily identified which impact CD4 T cells, it has been a challenging task to identify adjuvants that can amplify CD8 T cell responses. In this regard, Interleukin 33 (IL-33) and Interferon Stimulated Gene 15 (ISG15) have emerged as immunomodulatory molecules facilitating the generation of TH1-mediated T cell immunity; however, their ability to function as vaccine adjuvants to enhance CD8 T cell immunity was not previously explored. Here we used a DNA-vaccination approach to investigate the effect of IL-33 and/or ISG15 on vaccine-induced CD8 T cell immune responses. My studies showed that both IL-33 and ISG15 served as effective vaccine adjuvants to enhance the antigen-specific, polyfunctional, and cytolytic effector CD8 T cell responses in vivo. Importantly, I demonstrate for the first time the efficacy of both IL-33 and ISG15 as DNA vaccine adjuvants in driving viral or tumor protective immunity. Consideration of our findings, combined with a further understanding of the functional roles of these molecular adjuvants in immune expansion, likely will aid in the development of therapies for augmenting T cell based responses against many infectious diseases and cancers.