Loss of MHC class I (MHC-I) antigen presentation in cancer cells leads to evasion of CD8+ T-cell mediated immune surveillance and is associated with resistance to immune checkpoint blockade. Using genome-scale CRISPR/Cas9 screening we have identified a critical role for polycomb repressive complex 2 (PRC2) in the coordinated transcriptional silencing of the MHC-I antigen processing pathway in a range of cancers. Genetic disruption or pharmacological inhibition of PRC2 restores MHC-I antigen presentation allowing effective tumour targeting by CD8+ T-cells. I will discuss the molecular mechanisms governing MHC-I repression both during normal development and in cancer and describe how cancer cells co-opt an evolutionarily conserved, lineage specific function of an epigenetic complex to evade immune surveillance. Our findings suggest that resistance to cancer immunotherapies may occur not only through genomic mutations that inactivate MHC-I antigen presentation but also through non-genomic mechanisms that exploit the activity of repressive chromatin complexes such as PRC2.