IFN-γ is a pleiotropic cytokine crucial for both innate and adaptive immunity, which also plays a critical role in immunological surveillance of cancer. Genetic defects or gene silencing in the IFN-γ signal transduction pathways as well as in the expression of IFN-γ-regulated genes represent frequent mechanisms by which tumour cells can escape from immune responses. Epigenetic control of the IFN-γ signalling pathway activation associated with epigenetic changes in the corresponding regulatory gene regions, such as chromatin remodelling, histone acetylation and methylation, and DNA demethylation is frequently dysregulated in tumour cells. Epigenetic silencing of the IFN-γ regulatory pathway components, as well as of the IFN-γ-regulated genes crucial for tumour cell recognition or induction of anti-tumour immune responses, has been documented in various cancer models. Expression of both IFN-γ signalling pathway components and selected IFN-γ-regulated genes can be influenced by epigenetic modifiers, namely DNA methyltransferase and histone deacetylase inhibitors. These agents thus can mimic, restore, or boost the immunomodulatory effects of IFN-γ in tumour cells, which can contribute to their anti-tumour therapeutic efficacies and justifies their potential use in combined epigenetic therapy with immunotherapeutic approaches. and Corresponding author: Milan Reiniš