In healthy adult brain, glial cell line-derived neurotrophic factor (GDNF) is exclusively expressed by neurons and in some instances, it has furthermore been shown to derive from a single neuronal subpopulation. Secreted GDNF acts in a paracrine fashion by forming a complex with GDNF family receptor α1 (GFRα1) which is mainly expressed by neurons and can act in cis as a membrane-bound or in trans as a soluble factor. The GDNF/GFRα1 complex signals through interaction with RET (“rearranged during transfection”) or with a lower affinity with neural cell adhesion molecule (NCAM). GDNF can also signal independently from GFRα1 via interaction with syndecan-3. RET being expressed by neurons involved in several pathways: nigro-striatal dopaminergic neurons, motor neurons, enteric neurons, sensory neurons, etc. could be the main determinant of the specificity of GDNF pro-survival effect. In injured brain, de novo expression of GDNF occurs in glial cells. Neuroinflammation has been reported to induce GDNF expression in activated astrocytes and microglia, infiltrating macrophages, nestin-positive neural stem cells and neuron/glia (NG2) progenitors. This disease-related GDNF overexpression can be either beneficial or detrimental depending on the localization in the brain and the level and duration of glial cells activation. Some reports also describe upregulation of RET and GFRα1 in glial cells, suggesting that GDNF could modulate neuroinflammation.