Control and treatment of chronic pain remain major clinical challenges. Progress may be facilitated by a greater understanding of the mechanisms underlying pain processing. Here we show that the calcium-sensing protein DREAM is a transcriptional repressor involved in modulating pain. dream^−/− mice displayed markedly reduced responses in models of acute thermal, mechanical, and visceral pain. dream^−/− mice also exhibited reduced pain behaviors in models of chronic neuropathic and inflammatory pain. However, dream^−/− mice showed no major defects in motor function or learning and memory. Mice lacking DREAM had elevated levels of prodynorphin mRNA and dynorphin A peptides in the spinal cord, and the reduction of pain behaviors in dream^−/− mice was mediated through dynorphin-selective kappa (κ)-opiate receptors. Thus, DREAM appears to be a critical transcriptional repressor in pain processing.