Type 1 diabetes mellitus (T1DM) is the result of autoimmune destruction of pancreatic β cells in genetically predisposed individuals with impaired immune regulation. The insufficiency in the modulation of immune attacks on the β cells might be partly due to genetic causes; indeed, several of the genetic variants that predispose individuals to T1DM have functional features of impaired immune regulation. Whilst defects in immune regulation in patients with T1DM have been identified, many patients seem to have immune regulatory capacities that are indistinguishable from those of healthy individuals. Insight into the regulation of islet autoimmunity might enable us to restore immune imbalances with therapeutic interventions. In this Review, we discuss the current knowledge on immune regulation and dysfunction in humans that is the basis of tissue-specific immune regulation as an alternative to generalized immune suppression.