SETD2, the sole known HMT to create the histone H3 lysine 36 trimethyl (H3K36me3) modification through this histone change, mediates multiple molecular processes of gene regulation and DNA damage response. SETD2 also has nonhistone substrates with important roles in cellular homeostasis. Loss of SETD2 activity therefore may interrupt a host of critical processes that contribute to malignancy.