Although there is a general consensus on the great successes of genome sequencing and profile definition for several pediatric cancers, most overviews acknowledge that therapeutic applications are disappointing. Therefore a reassessment of the field seems to be necessary. The scope of this overview will be limited to paediatric leukemias and to CNS and peripheral nervous system tumors (i.e., Neuroblastoma –NB), which however constitute, combined, the majority of cancers in children. Pan-Cancer-Analysis (PCA) has documented for the first time the presence of point-mutations or other structural alterations in over 2.500 pediatric cancers. A few mean conclusions can be already drawn:

1.NGS-Era modeling should be implemented, taking into account molecular biology past contradictions and paradoxes;

2.The larger PCA study from St. Jude Children Hospital pinpointed 11 different signatures (for example linked to UVlight, APOBEC mutagenesis, etc.) potentially etiologic. This is in strident contrast with adult cancer, where a model of “bad-luck” relinquishes etiology as essentially irrelevant.

3.Etiological studies, especially in pediatric cancer, should be revived since new mutations affecting driver-genes have been clearly demonstrated in perfectly normal cells.

4.Major criticism toward a simple search for druggable-targets comes from innumerable studies, which have documented Tumor Heterogeneity (TH: both interand intra-tumor) in aggressive cancers (see Rovigatti 2015, 2016);

5.A new vista and approach toward cancer modeling, especially in pediatric cancer, is strongly recommended. It suggests alternative mechanisms to the reductionist approach of HoC, that should be investigated, for discovering comprehensive etiologic mechanisms and efficacious therapies in pediatric cancer.