The article identifies the anaplastic lymphoma kinase (ALK) gene as the major familial predisposition gene for neuroblastoma, a childhood cancer. Germline mutations in ALK explain the majority of hereditary neuroblastomas, and activating mutations can also be somatically acquired. A genome-wide scan in neuroblastoma pedigrees identified a significant linkage signal at chromosome 2p, and resequencing of candidate genes revealed three missense mutations in the ALK tyrosine kinase domain that segregated with the disease in eight families. Analysis of 491 sporadically occurring neuroblastoma samples showed that the ALK locus was gained in 22.8% and highly amplified in 3.3%, with these aberrations strongly associated with disease mortality. Resequencing of 194 high-risk neuroblastoma samples showed somatically acquired mutations in the ALK tyrosine kinase domain in 12.4%, with nine of ten mutations mapping to critical regions of the kinase domain and predicted to be oncogenic drivers. These mutations caused constitutive phosphorylation and targeted knockdown of ALK mRNA led to profound growth inhibition in cell lines harboring mutant or amplified ALK. The results demonstrate that heritable mutations in ALK are the major cause of familial neuroblastoma, and that germline or acquired activation of this kinase is a tractable therapeutic target. Neuroblastoma is a common childhood cancer with a wide range of clinical phenotypes, and while some cases are sporadic, a small subset is inherited. The study shows that ALK mutations are the primary cause of hereditary neuroblastoma, and that ALK activation is a promising therapeutic target for this lethal pediatric malignancy. The findings have significant implications for genetic screening and treatment strategies for neuroblastoma patients with a family history of the disease.The article identifies the anaplastic lymphoma kinase (ALK) gene as the major familial predisposition gene for neuroblastoma, a childhood cancer. Germline mutations in ALK explain the majority of hereditary neuroblastomas, and activating mutations can also be somatically acquired. A genome-wide scan in neuroblastoma pedigrees identified a significant linkage signal at chromosome 2p, and resequencing of candidate genes revealed three missense mutations in the ALK tyrosine kinase domain that segregated with the disease in eight families. Analysis of 491 sporadically occurring neuroblastoma samples showed that the ALK locus was gained in 22.8% and highly amplified in 3.3%, with these aberrations strongly associated with disease mortality. Resequencing of 194 high-risk neuroblastoma samples showed somatically acquired mutations in the ALK tyrosine kinase domain in 12.4%, with nine of ten mutations mapping to critical regions of the kinase domain and predicted to be oncogenic drivers. These mutations caused constitutive phosphorylation and targeted knockdown of ALK mRNA led to profound growth inhibition in cell lines harboring mutant or amplified ALK. The results demonstrate that heritable mutations in ALK are the major cause of familial neuroblastoma, and that germline or acquired activation of this kinase is a tractable therapeutic target. Neuroblastoma is a common childhood cancer with a wide range of clinical phenotypes, and while some cases are sporadic, a small subset is inherited. The study shows that ALK mutations are the primary cause of hereditary neuroblastoma, and that ALK activation is a promising therapeutic target for this lethal pediatric malignancy. The findings have significant implications for genetic screening and treatment strategies for neuroblastoma patients with a family history of the disease.