Enhancing β-Cell proliferation is a major goal for type 1 and type 2 diabetes research. Unraveling the network of β-Cell intracellular signaling pathways that promote β-Cell replication can provide the tools to address this important task. In a previous Perspectives in Diabetes article, we discussed what was known regarding several important intracellular signaling pathways in rodent β-Cells, including the insulin receptor substrate/phosphatidylinositol-3 kinase/Akt (IRS-PI3K-Akt) pathways, glycogen synthase kinase-3 (GSK3) and mammalian target of rapamycin (mTOR) S6 kinase pathways, protein kinase Cz (PKCz) pathways, and their downstream cell-cycle molecular targets, and contrasted that ample knowledge to the small amount of complementary data on human β-Cell intracellular signaling pathways. In this Perspectives, we summarize additional important information on signaling pathways activated by nutrients, such as glucose; growth factors, such as epidermal growth factor, platelet-derived growth factor, and Wnt; and hormones, such as leptin, estrogen, and progesterone, that are linked to rodent and human β-Cell proliferation. With these two Perspectives, we attempt to construct a brief summary of knowledge for β-Cell researchers on mitogenic signaling pathways and to emphasize how little is known regarding intracellular events linked to human β-Cell replication. This is a critical aspect in the long-term goal of expanding human β-Cells for the prevention and/or cure of type 1 and type 2 diabetes.