Neuroblastoma (NB) is a biological, genetic, and morphological heterogeneous neoplasm and demonstrates diverse clinical behavior. There exist at least three clinical patterns of NB: A) spontaneously regressing widespread disease; B) not metastatic local-regional disease, and C) metastatic disease (stage 4), frequently with lethal consequences. Patients with non-stage 4 NB are expected to survive even without medical treatment whereas stage 4 patients have an overall survival rate of 20% despite multimodality therapy protocols. The clinical management of patients with NB is therefore challenged by the objective identification of cases in which noncytotoxic approaches can be safely taken. Experience in the last decade at Memorial Sloan-Kettering Cancer Center supports the hypothesis that the natural history of disease defines relevant clinical groups of NB and has distinct molecular genetic profiles allowing therapeutic approaches tailored for each group. Here we review the natural history and clinicobiological features of 113 NB cases managed uniformly in our institution in an attempt to characterize useful genetic markers to support the decision making of noncytotoxic versus cytotoxic approaches for each category of NB.