Immune system modulation is evolving into a promising treatment modality in glioblastoma. Our growing understanding of glioma immunobiology has fueled efforts to develop immunotherapeutic strategies to combat this lethal primary brain tumor. Autologous stimulated lymphocytes, immunotherapy with cytokines and dendritic cells, immune checkpoint inhibitors, virotherapy, and tumor or peptide based vaccines are immunotherapy approaches under active investigation. A number of challenges are evident in the design of immunotherapy clinical trials in glioblastoma including patient selection, immune and imaging response monitoring, and evaluation of clinical outcome.