Diabetes Mellitus occurs in different clinical forms, however, all are characterized by a relative or absolute paucity of a functional pancreatic β-cell population to provide sufficient circulating insulin to maintain normal glucose homeostasis. Type 1 and Type 2 diabetes mellitus together are predicted to affect over 300 million people worldwide by the year 2020. While inadequate islet/β-cell mass is a central feature of both types of disease, identifying the pathways that mediate the embryonic origin of new β-cells and mechanisms that underlie the proliferation of existing β-cells are major efforts in the fields of developmental and islet biology. A poor response of existing b-cells to nutrients and hormones and the defects in hormone processing also contribute to the hyperglycemia observed in Type 2 diabetes and has prompted studies aimed at enhancing β-cell function. Moreover, insulin resistance, which usually occurs during the second trimester of pregnancy in gestational diabetic patients, progresses to levels seen in non-pregnant patients with Type 2 diabetes. Gestational diabetes is closely associated with altered pregnancy hormones and related factors that impact expansion of islet cell mass, insulin biosynthesis and/or glucose stimulated insulin secretion. In this chapter, we focus on recent work in the areas of islet/β-cell regeneration that are relevant to the pathophysiology of the endocrine pancreas in Type 1, Type 2 and gestational diabetes.