The islet of Langerhans (or pancreatic islet) is a unique endocrine organ that secretes multiple hormones that in turn orchestrate energy metabolism in humans. As in other metabolic organs, growth factor(s) regulate functional islet mass to maintain whole-body glucose homeostasis. Over the past decades, a large body of evidence has pointed to insulin and insulin-like growth factors (IGFs) as playing central roles in modulating diverse aspects of islet cell biology and a dysregulated insulin/IGF pathway has come to be recognized as a pathophysiological hallmark of type 2 diabetes (T2D). Several recent reports, especially focused on β-cells, highlight emerging aspects of insulin/IGF signaling, including a role for RNA modifications, transcriptional regulation by nuclear insulin and IGF-1 receptors, and the discovery of an insulin inhibitory receptor, inceptor. In this review, we summarize the functional roles of insulin/IGF signaling in regulating islet cell biology, the short- and long-term effects of insulin therapy in humans, and discuss potential strategies to maximize the beneficial effects of insulin action in islets to counter diabetes.