Repressive epigenetic modifications such as dimethylation and trimethylation histone H3 at lysine 9 (H3K9me2 and H3K9me3) and H3K27me3 have been shown to be critical for embryonic stem (ES) cell differentiation by silencing cell lineage-promiscuous genes. CD4(+) T helper (TH) cell differentiation is a powerful model to study the molecular mechanisms associated with cellular lineage choice in adult cells. Naïve TH cells have the capacity to differentiate into one of the several phenotypically and functionally distinct and stable lineages. Although some repressive epigenetic mechanisms have a critical role in TH cell differentiation in a similar manner to that in ES cells, it is clear that there are disparate functions for certain modifications between ES cells and TH cells. Here we review the role of repressive histone modifications in the differentiation and function of TH cells in health and disease.Immunology and Cell Biology advance online publication, 13 January 2015; doi:10.1038/icb.2014.115.