Testicular germ cell tumor (TGCT) is the most common malignancy in young men. Familial clustering, epidemiologic evidence of increased risk with family or personal history, and the association of TGCT with congenital genitourinary tract anomalies suggest an underlying genetic predisposition (1-6). Unfortunately, unraveling its genetic basis through traditional linkage studies has been difficult, in part because families with many affected individuals are exceedingly rare (7-10). Several cytogenetic abnormalities have been associated with sporadic TGCT, notably somatic isochromosome 12p in tumor tissue, and the germ-line chromosome abnormality 47,XXY (Klinefelter syndrome), which is associated with an increased risk of mediastinal germ cell tumors (11). Cytogenetic abnormalities have led to the localization of several hereditary cancer syndrome genes (e.g., retinoblastoma, Wilms tumor, and familial adenomatous polyposis; refs. 12-14). Given the paucity of data about potential genetic mechanisms in hereditary TGCT (HTGCT), we did conventional karyotype analysis and spectral karyotyping (SKY) in the largest cohort of HTGCT cases studied to date, seeking clues to the location of as-yet-unidentified testicular cancer susceptibility genes. We also provide a brief summary of previously reported cases and conclude that large-scale chromosome abnormalities are likely not the cause of the majority of HTGCT cases.