Members of the sirtuin family of protein deacetylases support and promote longevity in diverse organisms and can extend life span when upregulated. Sirtuin pathways also modulate fundamental mechanisms in aging-related neurodegenerative diseases, including protein aggregation, stress responses, mitochondrial homeostasis, and inflammatory processes. In this minireview, we will discuss how progress in understanding the neurobiology of sirtuins is shedding light on the pathogenesis of these devastating conditions. We will also examine the potential and challenges of targeting sirtuin pathways therapeutically.