Inadequate β-cell mass can lead to insulin insufficiency and diabetes. During times of prolonged metabolic demand for insulin, the endocrine pancreas can respond by increasing β-cell mass, both by increasing cell size and by changing the balance between β-cell proliferation and apoptosis. In this paper, we review recent advances in our understanding of the mechanisms that control the adaptive expansion of β-cell mass, focusing on the islet's response to pregnancy, a physiological state of insulin resistance. Functional characterization of factors controlling both β-cell proliferation and survival might not only lead to the development of successful therapeutic strategies to enhance the response of the β-cell to increased metabolic loads, but also improve islet transplantation regimens.