The heat shock protein (HSP) molecular chaperones are the primary cellular defense against damage to the proteome, initiating refolding of denatured proteins and regulating degradation after severe protein damage. Many neurodegenerative disorders involve aberrant protein folding and protein damage, which accumulates in an age-dependant manner. Ageing is associated with the decrease in activity of the heat shock transcription factors (HSF) that regulate HSP gene transcription. Neuronal cells seem particularly vulnerable in this sense as HSF activity and HSP expression are relatively weak in such cells and motor neurons appear to require input of HSP secreted from adjacent glial cells to maintain adequate molecular chaperone levels. It may be significant that motor neurons have been shown to be the sensitive cells in the ageing of Drosophila and C. elegans and that these organisms may acquire extended lifespans with over-expression of small heat shock proteins and HSF1. HSF1 transcriptional activity has been discussed in neuronal cells, concentrating on the regulation and activity of HSF1 and HSF2 and their role in HSP expression, during neurodegenerative diseases and as mediators of cell survival.