Differentiation is a key feature in pathologic classification and prognosis of neuroblastic tumors, although the underlying molecular mechanisms are not well defined. To identify key differentiation-related molecules and pathways, we evaluated gene expression during retinoic acid (RA)-induced differentiation of seven neuroblastic tumor cell lines. Transcriptional response to RA was highly variable among cell lines despite the fact that six of seven showed similar morphologic changes. RA consistently altered expression of a small set of genes, some of which are known to play a role in neurogenesis and differentiation. Expression of genes that were regulated by RA was associated with important clinical subgroups of neuroblastic tumors and were differentially expressed by stroma-rich and stroma-poor subtypes. RET, a receptor tyrosine kinase involved with differentiation, was consistently up-regulated throughout the time course of RA treatment in the majority of neuroblastic tumor cell lines. Interference with RET activation abrogated RA-induced transcriptional programs and differentiation, suggesting a key role of RET in this process. The core set of RA-regulated genes includes critical molecular components of pathways necessary for neuroblastic tumor differentiation and have potential as therapeutic targets and molecular markers of response to differentiating agents.