In multicellular eukaryotes, repression of gene transcription by Polycomb group (PcG) proteins is fundamental to cell fate determination and developmental transitions. Cis DNA motifs, called polycomb responsive elements (PREs), allow the recruitment of PcG proteins to their target genes, on which they deposit repressive epigenetic marks such as histone H3 lysine 27 trimethylation (H3K27me3). However, the understanding of the mechanisms controlling PcG recruitment is only fragmentary as certain genes do contain PREs in their promoter sequences and yet are ubiquitously transcribed implying that they are not targeted by, or refractory to PcG-mediated silencing. This raises the interesting possibility that unknown mechanisms actively protect certain genes from PcG-mediated silencing. We recently discovered that Plant Mobile Domain (PMD) proteins MAINTENANCE OF MERISTEMS (MAIN) and MAIN-LIKE1 (MAIL1) act in a same complex that is required for proper transcription of many genes in Arabidopsis thaliana. Unpublished data indicate that their evolutionary conserved paralog MAIN-LIKE2 (MAIL2) also regulates expression of several hundred genes. Our preliminary results strongly suggest that these PMD proteins secure the transcription of distinct sets of genes by antagonizing PcG-mediated silencing. The PolyPMD project combines genetics, genomics and biochemistry to unravel the mode of action of the PMD proteins in counteracting PcG-mediated gene repression. This will provide important new insights into a conserved mechanism of primary importance for the development of all multicellular organisms.