Parkinson’s disease (PD) is the second most common neurodegenerative disease after Alzheimer’s disease. The etiology of PD is still not completely understood, but degeneration of dopaminergic (DA) neurons in substantia nigra pars compacta (SNpc), loss of DA innervation of the striatum, and protein aggregates in form of Lewy bodies and neurites are established hallmarks. Besides α-synuclein accumulation in Lewy bodies and neurites, also genetic mutations in the genes encoding for example parkin, PINK, DJ-1 and LRRK2 proteins have been associated with the inherited form of PD and an association study linked also the receptor tyrosine kinas Ret with PD. Currently there are only symptomatic treatments available for PD and no cure. Therefore many efforts are made to find neurotrophic and other factors to stimulate SNpc DA neuron protection and regeneration. Glial cell line-derived neurotrophic factor (GDNF) is the founding member of the GDNF family of ligands (GFLs) including neurturin, artemin and persephin which belong to the transforming growth factor-β (TGF-β) superfamily. GDNF bindings with high affinity to GDNF family receptor α1 (GFRα1) that can subsequent activate the receptor tyrosine kinase Ret or alternative GDNF receptors such as the neuronal cell adhesion molecule NCAM, integrins αV and βI, syndecan-3 or N-cadherin. The canonical GDNF receptor Ret signals through many pathways such as the PI3K/Akt, Ras/MAPK, NF-κB, JNK, and PLC?/PKC pathways, while NCAM  can activate Fyn and FAK. GDNF is thought to be the most potent neurotrophic factor for the two midbrain dopaminergic (DA) neuron populations, the SNpc DA neurons dying in PD patients and the ventral tegmental area (VTA) DA neurons altered during drug addiction. Surprisingly, although GDNF stimulates neuronal differentiation, neurite outgrowth, synapse formation, and dopamine release in cell culture, GDNF was shown to be dispensable for DA neuron development and maintenance. In contrast, we could show in two different DA system specific Ret knockout mice, that Ret is dispensable during development but important for maintaining SNpc DA neurons in aging mice.