The chromatin environment is modulated by a machinery of chromatin modifiers, required for the specification and maintenance of cell fate. Many mutations in the machinery have been linked to the development and progression of cancer. In this review, we give a brief introduction to Polycomb group (PcG) proteins, their assembly into Polycomb repressive complexes (PRCs) and the normal physiological roles of these complexes with a focus on the PRC2. We review the many findings of mutations in the PRC2 coding genes, both loss-of-function and gain-of-function, associated with human cancers and discuss potential molecular mechanisms involved in the contribution of PRC2 mutations to cancer development and progression. Finally, we discuss some of the recent advances in developing and testing drugs targeting the PRC2 as well as emerging results from clinical trials using these drugs in the treatment of human cancers.