Neurodegenerative diseases including Alzheimers disease (AD) and Parkinsons disease (PD) afflict growing numbers of people but treatments are not available or ineffective. These diseases are characterized by the loss of specific neuronal populations, the accumulation of protein aggregates inside and sometimes outside neurons, and an activation of immune pathways in the brain. The causes of sporadic forms of AD or PD are not known but it has been postulated that reduced trophic support to neurons together with age dependent increases in cellular stress lead to chronic injury and ultimately the demise of neurons. TGF-βs are neuroprotective factors and organizers of injury responses and as such might have a role in neurodegenerative disease. We review here the evidence mostly from genetically manipulated mice that links the TGF-β signaling pathway to neuronal phenotypes and neurodegeneration. Although many of these mutant models did not produce overt CNS phenotypes or adult brain were not studied due to embryonic lethality, there is growing support for a role of TGF-β signaling in neuronal maintenance, function, and degeneration. Future studies will have to determine whether dysregulation of TGF-β signaling in neurodegenerative diseases is significant and whether this signaling pathway may even be a target for treatment.