For many decades, neuroblastoma has remained a challenging disease for both clinicians and researchers. Now, techniques that efficiently specify both comprehensive genetic and gene-expression alterations of neuroblastoma tumors have provided molecular markers that indicate tumor behavior and patient outcome with very high accuracy. Once the anticipated value of these markers has been confirmed in ongoing studies, patients may profit from more accurate risk assessment by integrating these markers into clinical routine. Moreover, disclosing further tumor-initiating events, such as the recently revealed oncogenic mutations of ALK, will further promote the elucidation of the genetic etiology of the disease. Together with recent information on altered signaling pathways in aggressively growing tumors, this knowledge will help to establish therapeutic strategies specifically targeting molecular key factors of neuroblastoma tumor progression.