I have been studying the biology of neuroblastoma for more than 25 years. Although neuroblastoma is a childhood cancer of the peripheral nervous system, the research on this tumor has contributed to fundamental understandings in cancer biology. For example, neuroblastoma is the first human malignant tumor where N-myc, a proto-oncogene was found amplified in primary tumors. During the past years, I have made several significant contributions to the field of cancer biology. (1) I have identified and characterized N-myc and L-myc proteins in neuroblastoma and small cell lung carcinoma, respectively, by epitope-defined monoclonal antibodies. Currently, the monoclonal antibody specific for N-myc (MYCN) is being considered for prognostic use to determine the aggressiveness of neuroblastoma. (2) Although the deletion of chromosome band 1p36 is a hallmark of neuroblastoma, there has been no identification of a particular tumor suppressor gene whose inactivation would be responsible for the development and progression of this tumor. My group and our collaborators have mapped and characterized candidate tumor suppressor genes of neuroblastoma, EPHA2 and ZBTB17, which are localized to this region of the chromosome 1. (3) My group has developed the concept of “Favorable Neuroblastoma Genes,” whose high-level expression predicts favorable outcome of neuroblastoma; we also showed that forced expression of these genes in unfavorable neuroblastoma cells confers growth suppression in vitro and in vivo. Subsequently, we showed that suppression of favorable neuroblastoma gene expression was due to epigenetic silencing and that inhibitors of DNA methylation and histone deacetylation could reverse the silencing of those genes. (4) We have solved a long-standing enigma in neuroblastoma: the relationship between MYCN expression and the prognostic outcome of neuroblastoma patients. In essence, the effect of MYCN expression depends on whether or not neuroblastomas carry MYCN amplification; a high-level MYCN expression in non-MYCN amplified cases is in fact associated with good prognostic outcome. (5) To gain insight into the most aggressive type of neuroblastoma, we have generated phenotypically stabilized stem cell-like neuroblastoma cells by transiently exposing the cells with epigenetic modifiers. We hence call the cells induced cancer stem cells (iCSC). Importantly, these cells recapitulated in vivo the histological appearance of large cell neuroblastoma that is among the most aggressive and deadly form of neuroblastoma. (6) Finally, our recent study reveals that aggressive neuroblastomas with high levels of MYC family protein expression often show a few prominent and hypertrophic nucleoli. To achieve this, neuroblastoma cells open up chromatin at rRNA genes, which are transcriptionally activated by the transcription factors and RNA Polymerase I (Pol I). The MYC/MAX complex binds E-boxes near rRNA genes and recruit histone acetyl transferases, allowing open chromatin configuration. MYC/MAX also up-regulates the expression of transcription factors of rRNA gene transcription. Hence, the emergence of prominent nucleoli suggests elevated MYC family protein expression and a hyperactive state of protein translation in NB cells. Based on these observations, we are developing strategies to target hyperactive protein translation machineries to combat highly aggressive MYC family protein-driven NB.