The median survival of patients with glioblastoma treated by surgery, radiotherapy and chemotherapy is in the range of 12 months. These limits in the efficacy of current treatment modalities call for the development of novel therapeutic approaches targeting the specific biological features of this type of cancer. Glioblastomas are a rich source of immunosuppressive molecules which may interfere with immune recognition and rejection as well as clinical strategies of active immunotherapy. The most prominent glioblastoma-associated immunosuppressant is the cytokine, transforming growth factor (TGF)-beta, a multifunctional cytokine which not only interferes with multiple steps of afferent and efferent immune responses, but also stimulates migration, invasion and angiogenesis. The complex regulation of TGF-beta bioavailability includes its synthesis as a proprotein, proteolytic processing by furin-like proteases, assembly in a latent complex, and finally liberation from latency by multiple effector mechanisms, a process collectively referred to as activation. Several in vitro paradigms and rodent glioma models have been used to demonstrate that the antagonism of TGF-beta holds promise for the treatment of glioblastoma, employing antisense strategies, inhibition of pro-TGF-beta processing, scavenging TGF-beta by decorin, or blocking TGF-beta activity by specific TGF-beta receptor (TGF-betaR) I kinase antagonists. Moreover, the local application of TGF-beta(2) antisense oligonucleotides is currently evaluated in a randomized clinical trial for recurrent malignant glioma. In summary, we propose that TGF-beta-antagonistic treatment strategies are among the most promising of the current innovative approaches for glioblastoma, particularly in conjunction with novel approaches of cellular immunotherapy and vaccination.