Characterization of the “T cell-inflamed” and “non-T cell-inflamed” tumor microenvironments has generated a framework for identifying immunotherapeutic targets and for understanding mechanisms of efficacy versus resistance. The T cell-inflamed phenotype includes expression of chemokines, T cell markers, and a type I IFN signature, whereas the non-T cell-inflamed phenotype lacks these factors and appears to display immune “exclusion”. The mechanisms of immune escape are likely distinct in these two subsets, and therefore the optimal immunotherapeutic interventions necessary to promote clinical responses may be different. The T cell-inflamed tumor microenvironment subset shows the highest expression of negative regulatory factors, including PD-L1, IDO, and FoxP3+ Tregs. Deep analysis of tumor antigen-specific T cells in the tumor microenvironment has identified additional mechanisms of immune dysfunction and new potential therapeutic targets. Treatment strategies targeting several pathways have been translated back into the clinic, with anti-PD-1/PD-L1 agents being FDA approved for over 14 different cancer entities. Combinations with new agents based on the biology of T cell dysfunction are ongoing. In contrast to the T cell-inflamed tumors, non-T cell-inflamed tumors are largely immunotherapy resistant with current approaches. Natural innate immune sensing of tumors appears to occur via the host STING pathway, type I IFN production, and cross-priming of T cells via Batf3-lineage DCs, and these factors are absent in non-T cell-inflamed tumors. New strategies are being developed to engage or mimic this pathway as a therapeutic endeavor, including STING agonists and other innate immune activators. The molecular mechanisms that mediate the absence of the T cell-inflamed tumor microenvironment in patients are being elucidated using parallel genomics platforms. The first oncogene pathway identified that mediates immune exclusion is the Wnt/-catenin pathway, which argues that new pharmacologic strategies to target this pathway should be developed to restore immune access to the tumor microenvironment. Several additional oncogenic events have also been identified that mediate immune escape that could be targeted therapeutically. Recent evidence has indicated that host factors, including germline genetic variants and the intestinal microbiota, are also critical mediators of the degree of endogenous immune priming and T cell infiltration into the tumor microenvironment. We recently have identified commensal bacteria in mouse models that augment spontaneous anti-tumor immunity and increase efficacy of anti-PD-L1 therapy. Similar analyses in human melanoma patients revealed commensal bacteria associated with anti-PD-1 efficacy in the clinic. These results have prompted the pursuit of new bacteria formulations that may improve spontaneous immune infiltration and expand immunotherapy efficacy.