Immunotherapy is emerging as a major treatment for patients with cancer, predominantly via blocking immune inhibitory pathways and through adoptive T cell therapy. However, only a subset of patients shows clinical responses to these interventions. Emerging data indicates a correlation between clinical response and a pre-existing T cell-inflamed tumor microenvironment. Tumor-intrinsic β-catenin activation has been identified as mediating exclusion of T cells from the tumor microenvironment and other oncogene pathways are being explored similarly. Understanding the molecular mechanisms underlying immune avoidance should identify new therapeutic targets for expanding efficacy of immunotherapies.