Neurotrophic factors (NTFs) have the unique potential to support neuronal survival and to augment neuronal function in the injured and diseased nervous system. Numerous studies conducted over the last 20 years have provided evidence for the potent therapeutic potential of NTFs in animal models of neurodegenerative diseases. However, major obstacles for the therapeutic use of NTFs are the inability to deliver proteins across the blood‐brain‐barrier, and dose‐limiting adverse effects resulting from the broad exposure of nontargeted structures to NTFs. Two recent developments have allowed NTFs’ promise to be truly tested for the first time: first, recent improvements in viral vectors that allow the targeted delivery of NTFs while providing a long‐lasting supply and sufficient therapeutic doses of NTFs; and second, improved animal models developed in recent years. In this review, we will discuss some of the potential therapeutic applications of NTFs in neurodegenerative diseases and the potential contribution of disturbed neurotrophic factor signaling to neurodegenerative diseases.