Disrupted Ca2+ homeostasis contributes to endoplasmic reticulum stress and has been implicated in Huntington disease (HD) pathogenesis. Here, Naranjo et al. report decreased expression of downstream regulatory element antagonist modulator (DREAM) — a member of the potassium channel-interacting protein subfamily of neuronal Ca2+ sensors that is important for Ca2+ homeostasis — in in vitro and in vivo mouse HD models, as well as in postmortem brain samples from patients with HD. This reduction in DREAM was found to be a neuroprotective, leading to derepression of activating transcription factor 6 signalling and activation of the prosurvival unfolded protein response. Chronic administration of the DREAM-binding antidiabetic drug repaglinide blocked DREAM activity in a mouse model of HD, delaying onset of motor dysfunction, reducing striatal atrophy and prolonging life span.