Gene regulation in human pancreatic endocrine cells is a complex process, governed by genetic and environmental factors and crosstalk between the various endocrine cell types, and between endocrine cells and the metabolic state. Recent advances in gene expression profiling, genome-wide analysis of epigenetic marks, and cell fractionation of human islets into their constitutive cell types have greatly increased our understanding of the complex processes that govern endocrine cell function in health and disease. Further progress in this area holds great promise for delivering new targets for the development of novel diabetes therapies.