Background: T cell-based immunotherapy is a promising treatment option for many cancer patients. In particular, immune checkpoint blockade and adoptive cell transfer regimens have led to remarkable clinical outcomes in patients with diverse tumor types. Despite these successes, however, many cancer patients fail to respond to immunotherapy, and others experience disease relapse shortly after an initial response. Recent insights from clinical and preclinical studies have yielded important information about tumor resistance to T cell-based immunotherapy, and these findings have paved the way for novel combinatorial approaches that aim to enhance the efficacy of anti-tumor T cell responses. Methods: A comprehensive PubMed literature search was performed to provide an up-to-date assessment of the field of combination T cell-based cancer immunotherapy. Keywords included in this search were “cancer,” “tumor,” “immune checkpoint blockade,” “adoptive cell transfer,” “chimeric antigen receptor,” “T lymphocyte,” “dendritic cell,” “cancer vaccine,” “immunogenic cell death,” “microbiome,” “metabolome,” “immune resistance,” and combinations thereof. Results: This chapter highlights diverse classes of combinatorial approaches for improving T lymphocyte-based cancer immunotherapy. Vaccination strategies and therapeutic regimens designed to support T cell activation via immunostimulatory dendritic cells are discussed, as are combination therapies that involve genetic manipulation of T lymphocytes or the coupling of checkpoint blockade with adoptive cell transfer. Interventions for manipulating the microbiome/metabolome to stimulate T lymphocyte activation are also highlighted. Finally, pharmacologic approaches for overcoming tumor-intrinsic resistance to T lymphocyte recognition and attack are described. Conclusions: Recent advances in our understanding of the biological drivers of tumor immune resistance have yielded insight into several potential targets for therapeutic interventions that aim to prevent or overcome tumor immune escape from T lymphocytes. Combination therapies that couple these strategies with traditional T cell-based cancer immunotherapies have the potential to significantly impact both the efficacy and reach of cancer immunotherapy in the years ahead.