Throughout life, organisms and their cells are subjected to various stressors which they must respond to adaptively in order to avoid disease and death. Accordingly, cells possess a variety of stress-responsive signaling pathways that are coupled to kinase cascades and transcription factors that induce the expression of genes that encode cytoprotective proteins such as protein chaperones (PC), growth factors and antioxidant enzymes. Emerging findings suggest that many of the environmental factors that improve health and so prolong lifespan (for example, dietary restriction, exercise and cognitive stimulation) exert their beneficial effects through a hormesis-like mechanism. Here we describe data supporting the hormesis hypothesis of disease resistance and longevity, with a focus on findings from studies of the nervous system in this laboratory.