Wilms tumor and neuroblastoma are childhood tumors of the kidney and undifferentiated neural crest cells, respectively. Both disorders are primarily sporadic, but familial Wilms tumor pedigrees and familial neuroblastoma pedigrees are each well recognized and account for approximately 1-3% of each tumor type. Families with Wilms tumor and neuroblastoma in the same, or related individuals, have not been reported. Here, we present nine families with two or more individuals with Wilms tumor and/or neuroblastoma. The affected individuals were otherwise well, without syndromic features. Although this co-occurrence might be due to chance in some families, the coexistence of two rare embryonal tumors in related individuals of multiple families suggests an underlying genetic susceptibility to both tumors. We undertook mutational analysis of the genes known to predispose to non-syndromic familial Wilms tumor (WT1) or neuroblastoma (PHOX2B, ALK) which excluded these as the underlying predisposition genes in the nine families. We also excluded epigenetic and copy-number abnormalities at 11p15 which are known to predispose to embryonal tumors including Wilms tumor and neuroblastoma. Overall, these data suggest that families with both Wilms tumor and neuroblastoma represent a previously unrecognized familial cancer syndrome in which the underlying predisposition gene(s) remain to be determined.