Glial cell line-derived neurotrophic factor (GDNF) is a potent survival factor, and a member of the transforming growth factor β (TGF-β) superfamily acting on different neuronal activities. GDNF was originally identified as a neurotrophic factor crucially involved in the survival of dopaminergic neurons of the nigrostriatal pathway and is currently an established therapeutic target in Parkinson’s disease. However, GDNF was later reported to be highly expressed in gliomas, especially in glioblastomas, and was demonstrated as a potent proliferation factor involved in the development and migration of gliomas. Here, we review our current understanding and progress made so far by researchers in our laboratories with references to relevant articles to support our discoveries. We present past and recent discoveries on the mechanisms involved in the protection of neurons by GDNF and examine its emerging roles in gliomas, as well as reasons for the abnormal expression in Glioblastoma Multiforme (GBM). Collectively, our work establishes a paradigm by which the ability of GDNF to protect dopaminergic neurons from degradation and its corresponding effects on glioma cells points to an underlying biological vulnerability in the effects of GDNF in the normal brain which can be subverted for use by cancer cells. Hence, presenting novel opportunities for intervention in glioma therapies.