Genetic fine mapping of 39 susceptibility loci — defined by genome-wide association studies — in 27,206 individuals with type 2 diabetes mellitus (T2DM) and 57,574 controls, has identified 49 distinct association signals, predominantly mapping to noncoding sequences. Comparison of these signals with chromatin immunoprecipitation sequence data identified a common role for hepatocyte nuclear factor 3β (HNF-3β, encoded by FOXA2) transcription-factor binding in the regulation of gene activity contributing to disease susceptibility. For example, an allelic variant associated with T2DM risk at the MTNR1B gene had higher HNF-3β transcriptional enhancer activity in human pancreatic islet and liver-derived cells than low-risk alleles. HNF-3β binding patterns could inform strategies for future research into the mechanisms underlying T2DM susceptibility.