Type 1 diabetes (T1D) is caused by T-cell-mediated destruction of the insulin-producing beta-cells in the pancreas. Genetic and immunological evidence from humans and mouse models indicates that CD4(+) T cells play a crucial role in the development and prevention of T1D. The dichotomy between CD4(+) T regulatory and effector T cells has encouraged research into the role of these cell subsets in T1D. New antigens and epitopes recognized by CD4(+) T cells in affected individuals have been identified. Growing knowledge of T-cell specificity and function is helping to develop new assays for analyzing islet antigen-specific CD4(+) T cells from human blood. Here we discuss, with particular reference to human studies, advances in our understanding of CD4(+) T-cell responses in T1D.