Aberrant cell cycle activity and DNA damage have been observed in neurons in association with various neurodegenerative conditions. While there is strong evidence for a causative role for these events in neurotoxicity, it is unclear how they are triggered and why they are toxic. Here, we introduce a brief background of the current view on cell cycle activity and DNA damage in neurons and speculate on their relevance to neuronal survival. Furthermore, we suggest that the two events may be triggered in common by deregulation of fundamental processes, such as chromatin modulation, which are required for maintaining both DNA integrity and proper regulation of cell cycle gene expression.