Polycomb-group (PcG) complexes are multiprotein, evolutionarily conserved epigenetic machineries that regulate stem cell fate decisions and development, and are also implicated in cancer and other maladies. The PcG machinery can be divided into two major complexes: Polycomb repressive complex 1 and 2 (PRC1 and PRC2). Traditionally, PcG complexes have been associated with maintenance of gene repression mainly via histone-modifying activities. However, during the last years, increasing evidence indicates that the PcG complexes can also positively regulate gene transcription and modify non-histone substrates in multiple biological processes, cellular stages, and cancers. In this review, we will illustrate recent findings in PcG-mediated gene regulation, with special focus on the recently described non-classical functions of PcG complexes in stem cells and cancer. Polycomb-group (PcG) proteins have diverse functions in cell differentiation and in cancers. PcG complexes have traditionally been prescribed roles as repressors of gene expression, though increasing evidence has demonstrated they can also activate transcription. PcG complexes post-translationally modify non-histone substrates and provide new potential targets for drug development. [ABSTRACT FROM AUTHOR]