The SET domain-containing protein 2 (SETD2, also known as HYPB) is a 230-kD protein that is located at cytogenetic band p21.31 of chromosome 3. SETD2 is usually transformed or eradicated in multiple forms of tumors in humans and may play important roles in the active gene transcription in human cells. The H3 lysine 36 histone methyltransferase SETD2 is mutated across a range of human cancers. Although other enzymes can mediate mono- and dimethylation, SETD2 is the exclusive trimethylase. SETD2 associates with the phosphorylated carboxy-terminal domain of RNA polymerase and modifies histones at actively transcribed genes. The functions associated with SETD2 are mediated through multiple effector proteins that bind trimethylated H3K36. SETD2, the sole histone H3K36 trimethyltransferase, is frequently mutated or deleted in human cancer, including pancreatic ductal adenocarcinoma (PDAC).