Aberrations in epigenetic processes, such as histone methylation, can cause cancer. Retinoblastoma binding protein 2 (RBP2; also called JARID1A or KDM5A) can demethylate tri- and dimethylated lysine 4 in histone H3, which are epigenetic marks for transcriptionally active chromatin, whereas the multiple endocrine neoplasia type 1 (MEN1) tumor suppressor promotes H3K4 methylation. Previous studies suggested that inhibition of RBP2 contributed to tumor suppression by the retinoblastoma protein (pRB). Here, we show that genetic ablation of Rbp2 decreases tumor formation and prolongs survival in Rb1+/− mice and Men1-defective mice. These studies link RBP2 histone demethylase activity to tumorigenesis and nominate RBP2 as a potential target for cancer therapy.National Institutes of Health (U.S.) (Grant CA138631)National Institutes of Health (U.S.) (Grant CA076120)National Institutes of Health (U.S.) (Grant CA16359)Raymond and Beverley Sackler Foundation (Fund for the Arts and Sciences)Caring for Carcinoid FoundationV Foundation for Cancer Research (V Scholar Award)Howard Hughes Medical Institute (Investigator)Doris Duke Charitable FoundationBreast Cancer AllianceAlexander and Margaret Stewart Trust