The Polycomb group (PcG) of repressors and the trithorax group (trxG) of activators maintain the correct expression of several key developmental regulators, including the homeotic genes. PcG and trxG proteins function in distinct multiprotein complexes that are believed to control transcription by changing the structure of chromatin, organizing it into either a 'closed' or an 'open' conformation. The hallmark of gene regulation by PcG/trxG proteins is that it can lead to a mitotically stable pattern of gene expression, often referred to as epigenetic regulation. Although much remains to be learned, recent studies have provided insights into how this epigenetic switch is set, how PcG/trxG proteins might be linked to cis-acting DNA elements and what potential mechanisms underlie stable inheritance of gene expression status over multiple cell divisions. Finally, the study of the evolutionarily conserved PcG/trxG factors has recently gained additional urgency with the realization that they play a pertinent role in certain human cancers.