Genetic screens in Drosophila have been instrumental in distinguishing approximately 390 loci involved in position effect variegation and heterochromatin stabilization. Most of the identified genes [so-called Su(var) and E(var) genes] are also conserved in mammals, where more than 50 of their gene products are known to localize to constitutive heterochromatin. From these proteins, approximately 12 core heterochromatin components can be inferred. In addition, there are approximately 30 additional Su(var) and 10 E(var) factors that can, under distinct developmental options, interchange with constitutive heterochromatin and participate in the partitioning of the genome into repressed and active chromatin domains. A significant fraction of the Su(var) and E(var) factors are enzymes that respond to environmental and metabolic signals, thereby allowing both the variation and propagation of epigenetic states to a dynamic chromatin template. Moreover, the misregulation of human SU(VAR) and E(VAR) function can advance cancer and many other human diseases including more complex disorders. As such, mammalian Su(var) and E(var) genes and their products provide a rich source of novel targets for diagnosis of and pharmaceutical intervention in many human diseases.