The c-Abl tyrosine kinase is implicated in diverse cellular activities including growth factor signaling, cell adhesion, oxidative stress, and DNA damage response. Studies in mouse models have shown that the kinases of the c-Abl family play a role in the development of the central nervous system. Recent reports show that aberrant c-Abl activation causes neuroinflammation and neuronal loss in the forebrain of transgenic adult mice. In line with these observations, an increased c-Abl activation is reported in human neurodegenerative pathologies, such as Parkinson's, and Alzheimer's diseases. This suggests that aberrant nonspecific posttranslational modifications induced by c-Abl may contribute to fuel the recurrent phenotypes/features linked to neurodegenerative disorders, such as an impaired mitochondrial function, oxidative stress, and accumulation of protein aggregates. Herein, we review some reports on c-Abl function in neuronal cells and we propose that modulation of different aspects of c-Abl signaling may contribute to mediate the molecular events at the interface between stress signaling, metabolic regulation, and DNA damage. Finally, we propose that this may have an impact in the development of new therapeutic strategies.