Understanding the biochemical and genetic alterations that occur during the aging of post-mitotic cells is critical for understanding the etiology of abnormalities observed during the aging of the central nervous system (CNS). While many theories for cellular aging exist, the free radical theory of aging has proved useful in explaining multiple aspects of post-mitotic cell aging, including the aging of neuronal cells. It is well established that Saccharomyces cerevisiae are an invaluable model system for exploring the regulation of aging in actively dividing cells, but increasing evidence suggests that the chronological lifespan or stationary phase model of aging in S. cerevisiae may also be useful for understanding the aging process in post-mitotic cells. Interestingly, the stationary phase model of aging in S. cerevisiae recapitulates many pathological alterations observed during neuronal aging, including evidence for increased oxidative stress and proteasome inhibition. Studies using proteins relevant to multiple neurodegenerative conditions (prion, alpha-synuclein, huntingtin) have demonstrated the utility of S. cerevisiae as a model system for understanding the genetic regulation of protein aggregation and cell death. Taken together, these data highlight the potential importance of using S. cerevisiae as a model system with which to explore the molecular basis for neuronal alterations observed in normal brain aging as well as multiple age-related diseases of the CNS.