Both humans and animal models provide many examples of highly heritable traits where the disease-causing genetic variants elude discovery. In these cases, heritability is often high but the explained genetic variance is low. The usual explanation involves undetected genetic variants with weak and heterogeneous actions in affected individuals. This explanation is reasonable given the limited statistical power in most genetic studies. However, we recently found several examples of heritable epigenetic changes, through the germline, suggesting that modes of inheritance other than DNA can also be transmitted across generations to affect phenotypic variation and disease risk. In each case, genetic variants in ancestral generations lead to phenotypic variation in subsequent generations. These effects can be as common and strong as those resulting from conventional inheritance, and they can persist for multiple generations. Transgenerational inheritance affects cancer, metabolic diseases, behaviors and many other traits. The effects are usually specific to one germ-lineage, with examples of transmission through the female germ-lineage and others through the paternal germ-lineage. The identity of the genes that mediate these effects implicate aspects of RNA biology including RNA editing, demethylation, translation control, and regulation of miRNA biology. These transgenerational effects challenge our understanding of inheritance and the origins of phenotypic variation and disease risk.