AT-rich interaction domain molecule 3B (ARID3B) and MYCN are expressed in a portion of neuroblastoma, and form a combination that has strong oncogenic activity in mouse embryonic fibroblasts (MEFs). Here, we show that this combination can also convert neural stem cells to neuroblastoma-like tumor. To address whether there are common mechanisms regulating the expression of this combination of genes, we examined public repositories of gene expression data and found that although these genes are rarely expressed together, co-expression was observed in a proportion of germ cell tumors (GCTs), in embryonic stem (ES) cells and in testis. These cell types and tissues are related to pluripotency and we show here that in mouse ES cells, Arid3b and Mycn are indeed involved in cell proliferation; the former in avoiding cell death and the latter in driving cell cycle progression. Accordingly, the two genes are induced during somatic cell reprogramming to iPS, and this induction is accompanied by the switching of promoter histone marks from H3K27me3 to H3K4me3. Conversely, the switch from H3K4me3 to H3K27me3 in these genes occurs during the differentiation of neural crest to mature sympathetic ganglia cells. In many, if not most, neuroblastomas these genes carry H3K4me3 marks within their promoters. Thus, a failure of the epigenetic silencing of these genes during development may be an underlying factor responsible for neuroblastoma.