Although genetic aberrations are essential in neuroblastoma (NB) development, its etiology and heterogeneity cannot be explained solely by genetics. NB arises due to defects in sympathetic neuron differentiation occurring during fetal development. Strikingly, the two factors promoting de-differentiation of NB cells, hypoxia and glucocorticoids, are elevated in the fetus during maternal stress, suggesting a role for prenatal stress in NB tumorigenesis. To test this hypothesis we used mice expressing MYCN under tyrosine hydroxylase promoter (TH-MYCN mice), which spontaneously develop NBs. To mimic stress, pregnant mothers carrying hemizygous TH-MYCN offspring were implanted with pellets containing either corticosterone or placebo at the time of neuroblast proliferation (E10-20). Tumor frequency was compared between these two experimental groups and TH-MYCN offspring from intact pregnancies. Surprisingly, in pregnant mothers from the placebo group, stress associated with experimental procedures alone was sufficient to elevate their corticosterone levels and increase tumorigenicity in their hemizygous TH-MYCN offspring from 32 to 64% (p = 0.03). A similar effect was observed in offspring of corticosterone-treated mothers with its levels comparable to mice eliciting a physiological stress response in the placebo group (<1200ng/ml). This stress-induced increase in tumorigenicity was associated with decreased tumor cell apoptosis, suggesting defects in neuroblast elimination as a potential mechanism underlying this effect. While all female mice presented with ovarian metastases, tumor-bearing prenatally stressed offspring had increased frequency of other distant metastases (0% vs 71% for intact control and stressed groups respectively, p<0.05). No increase in tumorigenicity was observed in offspring of corticosterone-treated mothers having corticosterone levels markedly exceeding those observed in the placebo group (>1200ng/ml), indicating that only physiologically relevant levels of stress mediators accurately recapitulate the stress response. These findings support the role for prenatal stress in NB development, as well as implicate other pathologies associated with elevated levels of glucocorticoids and fetal hypoxia in its etiology.