Finding therapies that can protect and expand functional b-cell mass is a major goal of diabetes research. Here, we generated b-cell–specific conditional knockout and gain-of-function mouse models and used human islet transplant experiments to examine how manipulating Nrf2 levels affects b-cell survival, proliferation, and mass. Depletion of Nrf2 in b-cells results in decreased glucose-stimulated b-cell proliferation ex vivo and decreased adaptive b-cell proliferation and b-cell mass expansion after a high-fat diet in vivo. Nrf2 protects b-cells from apo-ptosis after a high-fat diet. Nrf2 loss of function decreases Pdx1 abundance and insulin content. Activating Nrf2 in a b-cell–specific manner increases b-cell proliferation and mass and improves glucose tolerance. Human islets transplanted under the kidney capsule of immunocom-promised mice and treated systemically with bardoxolone methyl, an Nrf2 activator, display increased b-cell prolifer-ation. Thus, by managing reactive oxygen species levels, Nrf2 regulates b-cell mass and is an exciting therapeutic target for expanding and protecting b-cell mass in diabetes.