The increased burden of type 2 diabetes (T2D) necessitates the need for effective and safe novel drugs to treat this epidemic disease and its complications. By compiling this RDS Special Issue, our aim was to provide a comprehensive and critical overview on recent, ongoing, and future developments in this field. In collaboration with distinguished and renowned experts, we analyzed and discussed the most important advances in the field of incretin-based therapies, their extraglycemic effects, cardiovascular actions, and specific properties of the central nervous system. Another important drug class currently in development, the SGLT-2 inhibitors, and the role of the kidney in T2D are topics also covered by this issue. In addition to drug developments, new physiological insights into the understanding of the organ pathophysiology in T2D are presented that may eventually lead to additional therapeutic targets for obesity, T2D, and chronic inflammation acting on the brain, cardiovascular system, and pancreatic islets. The outcome of this Special Issue is a comprehensive reference work including bundled knowledge and expert opinions on the various aspects of the disease and its possible therapy strategies available now and in the near future. However, despite the advances delivered by modern incretin-based therapies today, there are still many limitations associated with efficacy data, application routes, and safety issues, which prevent the decline in diabetes complication rates. We conclude that further drug development and clinical trials are required to overcome these limitations, and to counteract the movement towards higher incidence rates of T2D and its complications.