Fifty years ago Jacob and Monod reported their findings on the regulation of gene activity. Working on lambda bacteriophage lysogeny and the regulation of the production of an enzyme that cleaves lactose, they observed that its production was induced by the presence of lactose in the medium and came to general conclusions about gene expression that still hold true today. Thanks to decades of intense multidisciplinary research, these conclusions have been extended by several fundamental discoveries. In particular, gene regulatory circuits include the ability to propagate the memory of a specific gene regulatory state long after being established and even when the original inducer is no longer present. Furthermore, in addition to being regulated by binding of regulators such as RNAs or proteins in the vicinity of the site of transcription initiation, genes can be regulated by factor binding at incredible distances from their transcriptional start sites. Prominent among the regulatory components involved in these processes are Polycomb and Trithorax group proteins, pleiotropic gene regulators of critical importance in development, physiology and disease.