Childhood neuroblastoma exhibits a heterogeneous clinical behavior ranging from low-risk tumors with the ability to spontaneously differentiate and regress, to high-risk tumors causing the highest number of cancer related deaths in infants. Amplification of the MYCN oncogene is one of the few prediction markers for adverse outcome. This gene encodes the MYCN transcriptional regulator predominantly expressed in the developing peripheral neural crest. MYCN is vital for proliferation, migration and stem cell homeostasis while decreased levels are associated with terminal neuronal differentiation. Interestingly, high-risk tumors without MYCN amplification frequently display increased c-MYC expression and/or activation of MYC signaling pathways. On the other hand, downregulation of MYCN leads to decreased proliferation and differentiation, emphasizing the importance of MYC signaling in neuroblastoma biology. Furthermore, expression of the neurotrophin receptor TrkA is associated with good prognosis, the ability to differentiate and spontaneous regression while expression of the related TrkB receptor is correlated with bad prognosis and MYCN amplification. Here we discuss the role of MYCN in neuroblastoma with a special focus on the contribution of elevated MYCN signaling for an aggressive and undifferentiated phenotype as well as the potential of using MYCN as a therapeutic target.