Neuroblastoma (NB) tumors with abundant Schwannian stroma have a differentiated phenotype, low vascularity, and are associated with a favorable prognosis. These observations have led to the hypothesis that ‘cross-talk’ between Schwann cells and neuroblasts influences the biology and clinical behavior of NB tumors. In support of this hypothesis, laboratory studies have shown that factors secreted by Schwann cells are capable of promoting NB differentiation, inhibiting angiogenesis, and impairing NB growth. Recently, using a novel NB xenograft model that was designed to directly investigate the affects of infiltrating Schwann cells, we demonstrated that infiltrating mouse Schwann cells can directly impact the phenotype of human NB xenografts in vivo. Taken together, these studies indicate that tumor–stroma interactions are critical in determining the biology of NB tumors. Further research investigating the molecules involved in the ‘cross-talk’ between Schwann cells and neuroblasts may lead to new treatment strategies that will modify tumor biology and alter the clinically aggressive nature of Schwannian stroma-poor NB tumors.