The unfolded protein response (UPR) is a highly conserved protein quality control mechanism, activated in response to Endoplasmic Reticulum (ER) stress. Signalling is mediated through three branches, PERK, IRE1, and ATF6, respectively, that together provide a coordinated response that contributes to overcoming disrupted proteostasis. PERK branch activation predominantly causes a rapid reduction in global rates of translation, while the IRE1 and ATF6 branch signalling induce a transcriptional response resulting in expression of chaperones and components of the protein degradation machinery. Protein misfolding neurodegenerative diseases show disruption of proteostasis as a biochemical feature. In the brains of animal models of disease and in human post mortem tissue from many of these disorders, markers of UPR induction, particularly, the PERK pathway can be observed in close association with disease progression. Recent research has revealed dysregulated UPR signalling to be a major pathogenic mechanism in neurodegeneration, and that genetic and pharmacological modulation of the PERK pathway results in potent neuroprotection. Targeting aberrant UPR signalling is the focus of new therapeutic strategies, which importantly could be beneficial across the broad spectrum of neurodegenerative diseases.