Type 2 diabetes mellitus (T2DM) results from pancreatic β-cell failure in the setting of insulin resistance. In the early stages of this disease, pancreatic β-cells meet increased insulin demand by both enhancing insulin-secretory capacity and increasing β-cell mass. As the disease progresses, β-cells fail to maintain these compensatory responses. This involves both extrinsic signals and mediators intrinsic to β-cells, which adversely affect β-cells by impairing insulin secretion, decreasing proliferative capacities, and ultimately causing apoptosis. In recent years, it has increasingly been recognized that changes in circulating levels of various factors from other organs play roles in β-cell dysfunction and cellular loss. In this review, we discuss current knowledge of interorgan communications underlying β-cell failure during the progression of T2DM.