Diabetes mellitus is an increasingly prevalent metabolic disorder that is estimated to affect over 300 million people by 2025. Common to either type 1 or type 2 diabetes is a progressive inadequacy of functional beta-cell mass. Recent studies have shown that during times of prolonged metabolic demand for insulin, the endocrine pancreas can respond by increasing beta-cell mass by beta-cell proliferation. Advances that further our knowledge of the molecular factors that control beta-cell proliferation will be crucial for understanding the homeostasis of beta-cell mass during adulthood, and are pivotal for any attempt to use instructive cues to induce the proliferation of terminally differentiated fully functional insulin-producing beta-cells that are suitable for transplantation. In the first part of my thesis, I investigated the role of CISH on beta cell proliferation in pregnant mice by using a pancreas-specific Cish-ablation mouse model. My results demonstrated that CISH is not required for beta cell proliferation or glucose homeostasis before, during, and after pregnancy. Socs2 expression is up-regulated in Cish-ablation islets at pregnant day 9.5, indicating that SOCS2 might be compensating for CISH deficiency. In the second part of my thesis, I studied the role of HNF4-alpha in beta cell proliferation during obesity by inducing beta-cell-specific Hnf4-alpha ablation in ob/ob mice. My results indicated that HNF4-alpha is required for beta-cell proliferation during obesity. Furthermore, I also demonstrated that overexpression of Hnf4-alpha in beta cells had no protective effect in glucose homeostasis in high-fat-diet fed obese mice. In the third part of my thesis, I investigated the role of betatrophin on human beta cell replication by transplanting human islets under kidney capsule of immunodeficient mice and induce betatrophin overexpressing in the liver. In spite of the mitogenic role of betatrophin on mouse beta-cells, it does not promote replication in human beta cells. In summary, my thesis work furthered the understanding of the role of CISH, HNF4-alpha, and betatrophin on beta-cell proliferation.