The genetic basis for susceptibility to testicular germ cell tumors (TGCTs) has been remarkably elusive. Although TGCTs are the most common cancer in young men and have an unusually strong familial risk, only one low-frequency susceptibility gene has been identified for this highly multigenic trait. In tests to determine whether pairs of genetic variants act epistatically to modulate susceptibility in the 129/Sv mouse model of spontaneous TGCTs, we discovered an unusual mode of inheritance that involved interactions between different genes in different generations. Any of six genetic variants, in either the female or male parent interacted with the Dnd1(Ter) mutation in male offspring to significantly increase both the frequency of affected Ter/+ males and the proportion of bilateral cases. Trans-generational epistasis is a novel mode of epigenetic inheritance that could account for the difficulty of finding TGCT susceptibility genes in humans and might represent a mechanism for transmitting information about genetic and environmental conditions from parents to offspring through the germline.