Due to their delicate locations as well as aggressive and infiltrative behavior, malignant brain tumors remain a therapeutic challenge. Harnessing the efficacy and specificity of the T-cell response to counteract malignant brain tumor progression and recurrence, represents an attractive treatment option. With the tremendous advances in the current era of immunotherapy, ongoing studies aim to determine the best treatment strategies for mounting a tumor-specific immune response against malignant brain tumors. However, immunosuppression in the local tumor environment, molecular and cellular heterogeneity as well as a lack of suitable targets for tumor-specific vaccination impede the successful implementation of immunotherapeutic treatment strategies in neuro-oncology. In this review, we therefore discuss the role of T cell exhaustion, the genetic and antigenic landscape, potential pitfalls and ongoing efforts to overcome the individual challenges in order to elicit a tumor-specific T cell response.