This article presents a comprehensive study on the genetic landscape of high-risk neuroblastoma, a malignant tumor of the sympathetic nervous system with a poor prognosis. The research, part of the TARGET initiative, analyzed 240 high-risk neuroblastoma cases using whole exome, genome, and transcriptome sequencing. The study found a low median exonic mutation frequency of 0.60 per megabase, with few recurrently mutated genes. Notable somatic mutations included *ALK* (9.2% of cases), *PTPN11* (2.9%), *ATRX* (2.5%), *MYCN* (1.7%), and *NRAS* (0.83%). Rare germline variants were significantly enriched in *ALK*, *CHEK2*, *PINK1*, and *BARD1*. The study highlights the limited number of recurrent somatic mutations in neuroblastoma, challenging current therapeutic strategies that rely on frequently altered oncogenic drivers. The findings suggest that high-risk neuroblastomas may be driven by rare germline variants, copy number alterations, and epigenetic modifications. The research underscores the need for further understanding of the interplay between host genetic factors, somatic mutations, chromosomal abnormalities, and epigenetic alterations in neuroblastoma.This article presents a comprehensive study on the genetic landscape of high-risk neuroblastoma, a malignant tumor of the sympathetic nervous system with a poor prognosis. The research, part of the TARGET initiative, analyzed 240 high-risk neuroblastoma cases using whole exome, genome, and transcriptome sequencing. The study found a low median exonic mutation frequency of 0.60 per megabase, with few recurrently mutated genes. Notable somatic mutations included *ALK* (9.2% of cases), *PTPN11* (2.9%), *ATRX* (2.5%), *MYCN* (1.7%), and *NRAS* (0.83%). Rare germline variants were significantly enriched in *ALK*, *CHEK2*, *PINK1*, and *BARD1*. The study highlights the limited number of recurrent somatic mutations in neuroblastoma, challenging current therapeutic strategies that rely on frequently altered oncogenic drivers. The findings suggest that high-risk neuroblastomas may be driven by rare germline variants, copy number alterations, and epigenetic modifications. The research underscores the need for further understanding of the interplay between host genetic factors, somatic mutations, chromosomal abnormalities, and epigenetic alterations in neuroblastoma.