We have previously shown that the expression of HDAC8 correlates with advanced tumor stage and poor outcome in neuroblastoma.15 Here, we verify small-molecule inhibition of HDAC8 as a novel therapeutic strategy alone and as a potent enhancer of retinoic acid-mediated differentiation and propose the cAMP-response element-binding protein (CREB) as a link between HDAC8 and retinoic acid-mediated gene transcription. Here, CREB1 is linked to neuroblastoma.