The islets of Langerhans harbor multiple endocrine cell types that continuously respond to circulating nutrient levels in order to adjust their secretion of catabolic and anabolic hormones. Stimulus-secretion coupling in these cells is largely of metabolic nature; that is, metabolism of nutrient fuels yields signals that trigger and amplify secretion of hormones. Hence, metabolism in this micro-organ is in a major way in control of whole-body metabolism. Therefore, insights into islet metabolism are critical to understand how secretion of insulin is regulated and why it is perturbed in type 2 diabetes. Metabolomics aims at characterizing a wide spectrum of metabolites in cells, tissues and body fluids. For this reason, this technique is well suited to supply information on stimulus-secretion coupling. Here, we summarize metabolomics studies in islets and β-cells, highlight important discoveries that would have been difficult to make without this technology but also raise awareness of challenges and bottlenecks that curtail its use in metabolic research.