This review summarizes the current knowledge on the expression and functional role of HLA-G in normal CNS cells and brain tumor cells in vitro and in vivo. The CNS has classically been viewed as an immune-privileged organ. Here we discuss some of the particularities of anti-tumoral responses within this compartment. Special emphasis is dedicated to the possible role of the non-classical MHC molecule HLA-G as an alternative mechanism of immune escape. We review the mechanisms how glioma cell-derived HLA-G may paralyze the immune system and which cellular subsets of the immune system are affected. Possible therapeutic implications derived from these observations include the targeting of HLA-G expression within the framework of inducing glioma-specific immunity.