Epigenetic regulation is a novel approach to cancer treatment. Inhibition of enhancer of zeste homolog 2 (EZH2) is a method to provide targeted epigenetic regulation. Tazemetostat is a first-in-class targeted epigenetic regulator that specifically inhibits EZH2. This new FDA-approved oral treatment received accelerated approval for patients with hematologic and solid malignancies. Tazemetostat was first approved for patients 16 years and older with metastatic or locally advanced epithelioid sarcoma not eligible for complete resection based on the results of an international open-label phase II basket trial. Another open-label multicenter phase II trial led to the approval for patients with relapsed or refractory follicular lymphoma with EZH2 mutation who have received at least two prior systemic therapies or patients who have no satisfactory alternative treatment options. Tazemetostat as an oral EZH2 inhibitor provides a new effective and tolerable treatment option for these patients.