Diabetes is a common multisystem disease that results in hyperglycemia due to a relative or absolute insulin deficiency. Improved glycemic control decreases the risk of development and progression of microvascular and, to a lesser extent, macrovascular complications and prevents symptomatic hyperglycemia. However, complex treatment regimens aimed at improving glycemic control are associated with an increased incidence of hypoglycemia. On paper at least, cellular therapies arising from reprogramed stem cells or other somatic cell types would provide ideal therapy for diabetes and the prevention of its complications. This hypothesis has led to intensive efforts to grow β cells from various sources. In this review, we provide an overview of β-cell development as well as the efforts reported to date in terms of cellular therapy for diabetes. Engineering β-cell replacement therapy requires an understanding of how β cells respond to other metabolites such as amino acids, free fatty acids, and ketones. Indeed, efforts thus far have been characterized by an inability of cellular replacement products to adequately respond to metabolites that normally couple the metabolic state to β-cell function and insulin secretion. Efforts to date intended to capitalize on current knowledge of islet cell development and stimulus-secretion coupling of the β cell are encouraging but as yet of little clinical relevance.