Intratumoral hypoxia followed by stabilization/activation of hypoxia-inducible factor 1 (HIF-1) and its downstream transcriptional factors, is one of the most important mechanisms inducing epithelial-mesenchymal transition (EMT), which has been widely accepted as a crucial step to generate early stage of tumor metastasis. Accumulating evidence suggests that epigenetic mechanisms play important roles in hypoxia-induced EMT and metastasis. These epigenetic regulations are mediated by various players including chromatin modifiers, transcriptional co-regulators, microRNAs, etc. In this review, we discuss how his tone-modifying enzymes and transcriptional co-regulators regulate EMT under hypoxic conditions. Developed or potential anticancer agents targeting epigenetic molecules regulating hypoxia-induced EMT are also discussed.