Little is known about the functions of downstream regulatory element antagonist modulator (DREAM) in embryonic stem cells (ESCs). However, DREAM interacts with cAMP response element-binding protein (CREB) in a Ca2+-dependent manner, preventing CREB binding protein (CBP) recruitment. Furthermore, CREB and CBP are involved in maintaining ESC self-renewal and pluripotency. However, a previous knockout study revealed the protective function of DREAM depletion in brain aging degeneration and that aging is accompanied by a progressive decline in stem cells (SCs) function. Interestingly, we found that DREAM is expressed in different cell types, including human ESCs (hESCs), human adipose-derived stromal cells (hASCs), human bone marrow-derived stromal cells (hBMSCs), and human newborn foreskin fibroblasts (hFFs), and that transitory inhibition of DREAM in hESCs reduces their pluripotency, increasing differentiation. We stipulate that these changes are partly mediated by increased CREB transcriptional activity. Overall, our data indicates that DREAM acts in the regulation of hESC pluripotency and could be a target to promote or prevent differentiation in embryonic cells.