Polycomb group (PcG) and trithorax group (trxG) proteins control the transcription of Hox and other target genes during development by binding to their respective response elements, which cluster in regulatory regions called maintenance elements (MEs). But do PcG and trxG proteins act synergistically at MEs? Not in most cases, claim Petruk et al., who have examined how trxG and PcG proteins associate with the ME of the bxd regulatory region of an Ultrabithorax (Ubx) transgene in individual Drosophila salivary gland cells in vivo (see p. 2383). Multiple trxG and PcG proteins, they report, act through the same or at juxtaposed sequences in the bxd ME. However, trxG or PcG proteins, but not both,associate with the ME of an activated or repressed Ubx transgene,respectively. Only the PcG protein Asx and the trxG protein Ash1 require Trithorax to bind to their targets. These results provide new insights into how PcG and trxG proteins might regulate transcription during development and during pathogenic processes such as cancer.