Epigenetic changes are the most common alterations in human cancer, but it has been difficult to sort out cause and effect from studies of human tumors. Several recent nonlethal mouse models implicate both hypomethylation and loss of imprinting (LOI) in tumor formation, including a paper in this issue of Cancer Cell showing that transient hypomethylation in ES cells causes LOI and liver and intestinal tumors (). Hypomethylation appears to be a critical determinant of cancer, affecting chromosomal stability and specific gene targets.